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Credit authorship contribution statement: Carolina R. Sanz: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft. Juliana Sarquis: Conceptualization, Data curation, Investigation, Writing – review & editing. María Ángeles Daza: Investigation, Methodology, Writing – review & editing. Guadalupe Miró: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – review & editing., Canine leishmaniosis (CanL), caused by Leishmania infantum, is a complex disease of growing importance in Europe. Clinical manifestations result from the down-modulation of the host immune response through multiple host-parasite interactions. Although several factors might influence CanL progression, this is the first known study evaluating risk factors for its different clinical stages in a large referral hospital population (n = 35.669) from an endemic area, over a 20 year period. Genome-wide scans for selection signatures were also conducted to explore the genomic component of clinical susceptibility to L. infantum infection. The prevalence of CanL was 3.2% (16.7% stage I; 43.6% stage II; 32.1% stage III; 7.6% stage IV). Dog breed (crossbreed), bodyweight (<10 kg), living conditions (indoors), regular deworming treatment, and being vaccinated against Leishmania significantly decreased the transmission risk and the risk for developing severe clinical forms. Conversely, the detection of comorbidities was associated with advanced clinical forms, particularly chronic kidney disease, neoplasia, cryptorchidism, infectious tracheobronchitis and urate urolithiasis, although those did not impact the clinical outcome. Significant associations between an increased risk of severe clinical stages and findings in the anamnesis (renal or skin-related manifestations) and physical examination (ocular findings) were also detected, highlighting their diagnostic value in referred cases of CanL. Sixteen breeds were found to be significantly more susceptible to developing severe stages of leishmaniosis (e.g. Great Dane, Rottweiler, English Springer Spaniel, Boxer, American Staffordshire Terrier, Golden Retriever), while 20 breeds displayed a clinical resistantance phenotype and, thus, are more likely to mount an efficient immune response against L. infantum (e.g. Pointer, Samoyed, Spanish Mastiff, Spanish Greyhound, English Setter, Siberian Husky). Genomic analyses of these breeds ret, Depto. de Sanidad Animal, Depto. de Medicina y Cirugía Animal, Fac. de Veterinaria, TRUE, pub

Aberrantly accumulated metabolites elicit intra- and inter-cellular pro-oncogenic cascades, yet current measurement methods require sample perturbation/disruption and lack spatio-temporal resolution, limiting our ability to fully characterize their function and distribution. Here, we show that Raman spectroscopy (RS) can directly detect fumarate in living cells in vivo and animal tissues ex vivo, and that RS can distinguish between Fumarate hydratase (Fh1)-deficient and Fh1-proficient cells based on fumarate concentration. Moreover, RS reveals the spatial compartmentalization of fumarate within cellular organelles in Fh1-deficient cells: consistent with disruptive methods, we observe the highest fumarate concentration (37 ± 19 mM) in mitochondria, where the TCA cycle operates, followed by the cytoplasm (24 ± 13 mM) and then the nucleus (9 ± 6 mM). Finally, we apply RS to tissues from an inducible mouse model of FH loss in the kidney, demonstrating RS can classify FH status. These results suggest RS could be adopted as a valuable tool for small molecule metabolic imaging, enabling in situ non-destructive evaluation of fumarate compartmentalization.

La leucemia linfoblastica acuta (LLA) è la neoplasia più frequente in età pediatrica, caratterizzata da un’eziologia multifattoriale. Studi recenti suggeriscono che 9n circa il 5% dei casi pediatrici di LLA.possa essere individuata una predisposizione genetica. Durante il percorso di dottorato, l’obiettivo della mia ricerca è stato quello di approfondire e caratterizzare il fenotipo e le caratteristiche biologiche di condizioni predisponenti la leucemia già note e di individuare nuove possibili associazioni tra predisposizione tumorale e LLA. Questa tesi è suddivisa in tre capitoli: nel primo vengono presentati i risultati di un'analisi retrospettiva di un'ampia coorte di individui con LLA ipodiploide, che confermano un’alta frequenza di mutazioni patogenetiche germinali di TP53. In questa categoria di pazienti abbiamo osservato un aumento del rischio di una storia familiare di cancro in età giovanile e una maggiore frequenza di secondi tumori maligni. Nel secondo capitolo, descriviamo un potenziale nuovo meccanismo predisponente la leucemia a cellue precursori B, identificando, per la prima volt,a in due fratelli con LLA BCP una variante frameshift germinale a carico di PAX5. Infine, abbiamo studiato l'impatto di due rare varianti germinali di STAG1 in due pazienti pediatrici rispettivamente affetti da LLA e sindrome mielodisplastica (MDS). Attraverso studi funzionali abbiamo dimostrato un’aumentata instabilità cromosomica compromessa e meccanismi di riparazione del DNA difettivi, suggerendo che queste varianti in STAG1 possano predisporre l’oncogenesi. L’obiettivo comune di questi tre lavori è quello di migliorare la comprensione dei fattori genetici che influenzano lo sviluppo delle neoplasie ematologiche, in particolare nella LLA pediatrica, con la convinzione che una migliore conoscenza e caratterizzazione delle alterazioni genetiche predisponenti possa cambiare la gestione dei pazienti ottimizzando le strategie di trattamento e i protocoll, Childhood acute lymphoblastic leukemia (ALL) is a hematologic malignancy with multifactorial origins. Recent evidence suggests that genetic predisposition may significantly influence approximately 5% of pediatric ALL cases. The goal of my research was to expand our understanding of disease phenotypes and uncover new associations between cancer predisposition and ALL. This work is divided into three distinct tasks: First, we present the results of a comprehensive analysis of a large cohort of low hypodiploid individuals ALL, confirming a high prevalence of deleterious TP53 germline mutations. These patients who carried a pathogenic TP53 germline variant showed an increased risk of a family history of cancer and a higher frequency of second malignancies. Our results highlight the importance of TP53 mutation testing for this category of patients. In the second chapter, we unveil a potentially diverse mechanism contributing to leukemogenesis by identifying the first germline frameshift of the PAX5 variant in a family with recurrent B-cell progenitors ALL. These discoveries illuminate a new avenue for studying leukemogenesis. Finally, we are investigating the impact of rare STAG1 germline variants in two pediatric patients with ALL and with myelodysplastic syndrome (MDS), respectively. We demonstrated impaired chromosome stability and defective DNA repair mechanisms. This evidence sheds light on how these variants may contribute to oncogenesis. Overall, we aimed to improve our understanding of the genetic factors that influence hematologic malignancies, particularly in pediatrics ALL. Better knowledge and characterization of predisposing genetic alterations could change the management of patients by optimizing treatment strategies and surveillance protocols.

Musical training has long been viewed as a model for experience-dependent brain plasticity. Reports of musical training-induced brain plasticity are largely based on cross-sectional studies comparing musicians to non-musicians, which cannot address whether musical training itself is sufficient to induce these neurobiological changes or whether pre-existing neuroarchitecture before training predisposes children to succeed in music. Here, in a longitudinal investigation of children from infancy to school age (n = 25), we find brain structure in infancy that predicts subsequent music aptitude skills at school-age. Building on prior evidence implicating white matter organization of the corticospinal tract as a neural predisposition for musical training in adults, here we find that structural organization of the right corticospinal tract in infancy is associated with school-age tonal and rhythmic musical aptitude skills. Moreover, within the corpus callosum, an inter-hemispheric white matter pathway traditionally linked with musical training, we find that structural organization of this pathway in infancy is associated with subsequent tonal music aptitude. Our findings suggest predispositions prior to the onset of musical training from as early as infancy may serve as a scaffold upon which ongoing musical experience can build. Research Highlights Structural organization of the right corticospinal tract in infancy is associated with school-age musical aptitude skills. Longitudinal associations between the right corticospinal tract in infancy and school-age rhythmic music aptitude skills remain significant even when controlling for language ability. Findings support the notion of predispositions for success in music, and suggest that musical predispositions likely build upon a neural structural scaffold established in infancy. Findings support the working hypothesis that a dynamic interaction between predisposition and experience established in infancy shape the trajectory

Recenti evidenze hanno dimostrato come la predisposizione rivesta un ruolo cruciale nel 5-10% dei tumori pediatrici. Ciò nonostante, è ancora un ambito nebuloso, che va ulteriormente investigato. Nell’adulto, l’evoluzione clonale agisce in modo simile: l’accumulo di mutazioni somatiche dovuto all’età, aumenta la prevalenza di neoplasie mieloidi tra gli individui più anziani. Come specifici pathway di co-occorrenza predispongano a tumori ematologici, è da indagare in modo più approfondito. In questo studio, ci siamo focalizzati sul ruolo della predisposizione genetica nei tumori ematologici del bambino e dell’adulto, allo scopo di migliorare le conoscenze riguardo alle alterazioni genetiche che agiscono nella fase pre-leucemica. Abbiamo realizzato il nostro studio attraverso diverse tasks, caratterizzate dall’obiettivo comune di scandagliare il ruolo della predisposizione genetica nel promuovere la trasformazione neoplastica. Innanzitutto, abbiamo sequenziato una corte di 120 diagnosi consecutive di pazienti pediatrici affetti da Leucemia Linfoblastica Acuta e casi sporadici con altri tumori ematologici, così come casi con ricorrenza familiare. Il profiling genetico ha confermato il ruolo cruciale di alcuni geni nella Leucemogenesi, come quelli appartenenti al pathway di RAS, sia in termini di incidenza, sia di patogenicità. Inoltre, ha fatto luce sulle mutazioni germinali nelle Coesine: queste alterazioni, solitamente associate a sindromi genetiche denominate Coesinopatie, non sono eventi sporadici, ma si presentano con una frequenza non trascurabile (6%) e degna di ulteriori approfondimenti. Considerando questa evidenza, ci siamo focalizzati sulle varianti germinali dei geni STAG1 e RAD21. I nostri risultati hanno dimostrato che queste alterazioni sono responsabili di una scarsa coesione cromatinica, promuovono quindi instabilità genetica spontanea e sono caratterizzati da meccanismi di riparo al danno del DNA difettivi. Pertanto, geni che non sono classic, Despite genetic predisposition occurs in 5-10 % of pediatric cancer, it is still a nebulous field, that has to be better characterized. In the adult setting, clonal evolution acts similarly, and age-dependent accumulation of somatic mutations increases the prevalence of myeloid neoplasms among older individuals. How the specific co-occurrence of somatic events predisposes to hematological malignancies have to be further clarified. In the present project, we focused our attention in dissecting the role of genetic predisposition in both childhood and adult hematological malignancies, with the purpose of improving knowledge about genetic alterations that act in pre-leukemic phase. We planned and developed our study through several tasks, characterized by the joint purpose of investigating the contribution of genetic predisposition in promote tumor transformation. Firstly, we screened a cohort of 120 consecutive diagnosis of pediatric patients affected by Acute Lymphoblastic Leukemia and sporadic cases with other hematological malignancies, as well as cases with familiar recurrence. Genetic profiling confirmed the crucial role of some genes in Leukemogenesis, like those belonging to Ras pathway, both in term of incidence and pathogenicity. Moreover, it shed light on germline mutations in Cohesins: these alterations, usually associated to genetic syndromes called Cohesinopathies, are not random or sporadic events, but occur with a frequency (6%) that is not negligible and worthy of further study. Considering this evidence, we made a focus on STAG1 and RAD21 germline variants. Our results demonstrated that they lead to a poor chromosomal strength and promote spontaneous instability, resulting in a lowered response to exogenous and endogenous agents, as well as defective DNA repair mechanisms. So, genes that are not classically related to full-blown stage of hematological disease, promote cancer prone conditions in pediatric patients, aggravating the risk of somatic events

Abstract Background Stratifying patients with sepsis was the basis of the predisposition, infection, response and organ dysfunction (PIRO) concept, an attempt to resolve the heterogeneity in treatment response. The purpose of this study is to perform an independent validation of the PIRO staging system in an international cohort and explore its utility in the identification of patients in whom time to antibiotic treatment is particularly important. Methods Prospective international cohort study, conducted over a 6-month period in five Portuguese hospitals and one Australian institution. All consecutive adult patients admitted to selected wards or the intensive care, with infections that met the CDC criteria for lower respiratory tract, urinary, intra-abdominal and bloodstream infections were included. Results There were 1638 patients included in the study. Patients who died in hospital presented with a higher PIRO score (10 ± 3 vs 8 ± 4, p < 0.001). The observed mortality was 3%, 15%, 24% and 34% in stage I, II, III and IV, respectively, which was within the predicted intervals of the original model, except for stage IV patients that presented a lower mortality. The hospital survival rate was 84%. The application of the PIRO staging system to the validation cohort resulted in a positive predictive value of 97% for stage I, 91% for stage II, 85% for stage III and 66% for stage IV. The area under the receiver operating characteristics curve (AUROC) was 0.75 for the all cohort and 0.70 if only patients with bacteremia were considered. Patients in stage III and IV who did not have antibiotic therapy administered within the desired time frame had higher mortality rate than those who have timely

It is not clear when and how animals start to discriminate between male and female conspecifics and how this distinction drives their social behaviour. A study on pheasants found that 1-week-old chicks (Phasianus colchicus) preferentially aggregated with same-sex peers and this trend became more pronounced through development, suggesting that sexual segregation increases during ontogeny. However, it remains unclear whether this ability depends on experience or develops spontaneously. Using a similar experimental protocol, we investigated whether sex discrimination is present at birth in domestic chickens (Gallus gallus) by testing the social preferences of young chicks with clutch mates. We measured the amount of time spent close to male and female conspecifics in visually inexperienced chicks. Soon after hatching, both males and females preferentially aggregated with females. To clarify whether the experience with conspecifics modifies the initial preference for females, we used an imprinting procedure. We exposed chicks to conspecifics of the same sex, different sex or both sexes for 3 days and then tested their preferences to aggregate with males or females. No sex preference was observed after 3 days of imprinting exposure. The disappearance of the initial sex preference shows that, although chicks can discriminate between conspecifics of different sex, sex segregation does not influence sex preferences in the first week of life. We suggest that the absence of sexual assortment in the first week of age can enhance the social cohesion of the flock. Significant statement: The ability to discriminate males from females affects a wide range of social behaviours, including the preferences for own sex conspecifics during sex segregation and the choice of a partner in the mating period. However, it remains unclear when and how males and females start to discriminate members of the same/different sex. We tested the domestic chicks to explore whether sex discri

Tato bakalářská práce se zabývá problematikou celikalie, včetně její diagnostiky. Teoretická část této práce je zaměřena na obecnou charakteristiku tohoto onemocnění, klinické projevy celiakie a jejich řešení. Detailně se teoretická část této práce zaměřuje na možnosti diagnostiky a léčby. Experimentální část této práce je věnována metodám genetického vyšetření predispozic celiakie pomocí určení alel HLA asociovaných celiakií, nejčastěji HLA-DQ2 a HLA-DQ8. Tato část práce se dále zabývá popisem těchto metod a interpretací výsledků měření jednotlivých vzorků., This bachelor thesis is focused on problematics of coeliac disease including its diagnostics. The theoretical part is dedicated to basic characteristics of the disease, description of clinical manifestation and its solution. In detail, the theoretical part deals with options of diagnostics and the treatment. The aim of experimental methodological part of this thesis is examination of genetics of coeliac disease predisposition by idetification of HLA allele. HLA- DQ2 and HLA-DQ8 are most typically associated with the coeliatic disease. This part is also involves description of methods and results interpretation., Fakulta chemicko-technologická, 1. Prezentace výsledků bakalářské práce. 2. Diskuze k posudku vedoucího bakalářské práce. 3. Studentka zodpověděla všechny dotazy a připomínky k BP., Dokončená práce s úspěšnou obhajobou

BACKGROUND: Recent whole genome sequencing studies report that up to 6% of the childhood cancer population harbour a pathogenic variant. Identification of families with hereditary cancer may improve early detection of cancer as well as treatment outcome. AIMS: The overall aim of this thesis was to investigate familial cancer risk in relatives of children with cancer and assess the prevalence of pathogenic germline variants.METHODS: Pediatric cancer patients included in the Lund Childhood Cancer Genetic study provided blood samples after informed consent. The Swedish Population- and Cancer Register were used to identify relatives with cancer diagnoses up to the third degree of relation. The relative risk for relatives was calculated. Illumina HiSeq 2500 was used to sequence DNA from patient blood for 22 cancer predisposition genes.RESULTS: Study I: 41/528 families (7.8%) had multiple pediatric cancer cases up to the third degree of relation. Related children with cancer often had the same cancer diagnosis and were more likely to be female. Study II: We report an increased risk for adult cancer (SIR 1.07) and pediatric cancer (SIR 1.48) in 16,430 relatives of 757 children with cancer up to the third degree of relation. The results were unchanged when excluding 30 families of children with known germline pathogenic variants. Study III: Among 790 children with cancer, 3.8% carried one of the 22 most frequent pathogenic germline variants, resulting in 4.9% when correcting for diagnosis distribution. The prevalence of pathogenic variants for childhood cancer diagnoses was in line with recent whole genomic sequencing studies. CONCLUSIONS: Family members of children with cancer have an increased cancer risk compared to the general population, which is not explained by known pathogenic germline variants alone. This thesis supports the need for further studies on genomics as well as other potential causes of pediatric and familial cancer.

Multigene panels are routinely used to assess for predisposing germline mutations in families at high breast cancer risk. The number of variants of unknown significance thereby identified increases with the number of sequenced genes. We aimed to determine whether tumor sequencing can help refine the analysis of germline variants based on second somatic genetic events in the same gene. Whole-exome sequencing (WES) was performed on whole blood DNA from 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53, or CHEK2 mutation. Rare variants were retained in a list of 735 genes. WES was performed on matched tumor DNA to identify somatic second hits (copy number alterations (CNAs) or mutations) in the same genes. Distinct methods (among which immunohistochemistry, mutational signatures, homologous recombination deficiency, and tumor mutation burden analyses) were used to further study the role of the variants in tumor development, as appropriate. Sixty-eight patients (97%) carried at least one germline variant (4.7 ± 2.0 variants per patient). Of the 329 variants, 55 (17%) presented a second hit in paired tumor tissue. Of these, 53 were CNAs, resulting in tumor enrichment (28 variants) or depletion (25 variants) of the germline variant. Eleven patients received variant disclosure, with clinical measures for five of them. Seven variants in breast cancer-predisposing genes were considered not implicated in oncogenesis. One patient presented significant tumor enrichment of a germline variant in the oncogene ERBB2, in vitro expression of which caused downstream signaling pathway activation. Tumor sequencing is a powerful approach to refine variant interpretation in cancer-predisposing genes in high-risk breast cancer patients. In this series, the strategy provided clinically relevant information for 11 out of 70 patients (16%), adapted to the considered gene and the familial clinical phenotype.

Global climate change is expected to further raise the frequency and severity of extreme events, such as droughts. The effects of extreme droughts on trees are difficult to disentangle given the inherent complexity of drought events (frequency, severity, duration, and timing during the growing season). Besides, drought effects might be modulated by trees’ phenotypic variability, which is, in turn, affected by long-term local selective pressures and management legacies. Here we investigated the magnitude and the temporal changes of tree-level resilience (i.e., resistance, recovery, and resilience) to extreme droughts. Moreover, we assessed the tree-, site-, and drought-related factors and their interactions driving the tree-level resilience to extreme droughts. We used a tree-ring network of the widely distributed Scots pine (Pinus sylvestris) along a 2,800 km latitudinal gradient from southern Spain to northern Germany. We found that the resilience to extreme drought decreased in mid-elevation and low productivity sites from 1980–1999 to 2000–2011 likely due to more frequent and severe droughts in the later period. Our study showed that the impact of drought on tree-level resilience was not dependent on its latitudinal location, but rather on the type of sites trees were growing at and on their growth performances (i.e., magnitude and variability of growth) during the predrought period. We found significant interactive effects between drought duration and tree growth prior to drought, suggesting that Scots pine trees with higher magnitude and variability of growth in the long term are more vulnerable to long and severe droughts. Moreover, our results indicate that Scots pine trees that experienced more frequent droughts over the long-term were less resistant to extreme droughts. We, therefore, conclude that the physiological resilience to extreme droughts might be constrained by their growth prior to drought, and that more frequent and longer drought periods may ove

Study Objectives: There is little information about familial aggregation of insomnia; however, this type of information is important to (1) improve our understanding of insomnia risk factors and (2) to design more effective treatment and prevention programs. This study aimed to investigate evidence of familial aggregation of insomnia among first-degree relatives of probands with and without insomnia. Methods: Cases (n = 134) and controls (n = 145) enrolled in a larger epidemiological study were solicited to invite their first-degree relatives and spouses to complete a standardized sleep/insomnia survey. In total, 371 first-degree relatives (Mage = 51.9 years, SD = 18.0; 34.3% male) and 138 spouses (Mage = 55.5 years, SD = 12.2; 68.1% male) completed the survey assessing the nature, severity, and frequency of sleep disturbances. The dependent variable was insomnia in first-degree relatives and spouses. Familial aggregation was claimed if the risk of insomnia was significantly higher in the exposed (relatives of cases) compared to the unexposed cohort (relatives of controls). The risk of insomnia was also compared between spouses in the exposed (spouses of cases) and unexposed cohort (spouses of controls). Results: The risk of insomnia in exposed and unexposed biological relatives was 18.6% and 10.4%, respectively, yielding a relative risk (RR) of 1.80 (p = .04) after controlling for age and sex. The risk of insomnia in exposed and unexposed spouses was 9.1% and 4.2%, respectively; however, corresponding RR of 2.13 (p = .28) did not differ significantly. Conclusions: Results demonstrate evidence of strong familial aggregation of insomnia. Additional research is warranted to further clarify and disentangle the relative contribution of genetic and environmental factors in insomnia.

Background: Multigene panels are routinely used to assess for predisposing germline mutations in families at high breast cancer risk. The number of variants of unknown significance thereby identified increases with the number of sequenced genes. We aimed to determine whether tumor sequencing can help refine the analysis of germline variants based on second somatic genetic events in the same gene. Methods: Whole-exome sequencing (WES) was performed on whole blood DNA from 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53, or CHEK2 mutation. Rare variants were retained in a list of 735 genes. WES was performed on matched tumor DNA to identify somatic second hits (copy number alterations (CNAs) or mutations) in the same genes. Distinct methods (among which immunohistochemistry, mutational signatures, homologous recombination deficiency, and tumor mutation burden analyses) were used to further study the role of the variants in tumor development, as appropriate. Results: Sixty-eight patients (97%) carried at least one germline variant (4.7 ± 2.0 variants per patient). Of the 329 variants, 55 (17%) presented a second hit in paired tumor tissue. Of these, 53 were CNAs, resulting in tumor enrichment (28 variants) or depletion (25 variants) of the germline variant. Eleven patients received variant disclosure, with clinical measures for five of them. Seven variants in breast cancer-predisposing genes were considered not implicated in oncogenesis. One patient presented significant tumor enrichment of a germline variant in the oncogene ERBB2, in vitro expression of which caused downstream signaling pathway activation. Conclusion: Tumor sequencing is a powerful approach to refine variant interpretation in cancer-predisposing genes in high-risk breast cancer patients. In this series, the strategy provided clinically relevant information for 11 out of 70 patients (16%), adapted to the considered gene and the familial clinical phenoty, SCOPUS: ar.j, info:eu-repo/semantics/published

Colorectal cancer (CRC) is a complex disorder for which the majority of the underlying germline predisposition factors remain still unidentified. Here, we combined whole-exome sequencing (WES) and linkage analysis in families with multiple relatives affected by CRC to identify candidate genes harboring rare variants with potential high-penetrance effects. Forty-seven affected subjects from 18 extended CRC families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. Suggestive linkage peaks were identified on chromosomes 1q22-q24.2 (maxSNP = rs2134095; LODlinear = 2.38, LODexp = 2.196), 7q31.2-q34 (maxSNP = rs6953296; LODlinear = 2.197, LODexp = 2.149) and 10q21.2-q23.1 (maxSNP = rs1904589; LODlinear = 1.445, LODexp = 2.195). These linkage signals were replicated in 10 independent sets of random markers from each of these regions. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 89 rare variants predicted to be deleterious from 78 genes under the linkage intervals. This analysis showed significant segregation of rare variants with CRC in 18 genes (weighted p-value > 0.0028). Protein network analysis and functional evaluation were used to suggest a plausible candidate gene for germline CRC predisposition. Etiologic rare variants implicated in cancer germline predisposition may be identified by combining traditional linkage with WES data. This approach can be used with already available NGS data from families with several sequenced members to further identify candidate genes involved germline predisposition to disease. This approach resulted in one candidate gene associated with increased risk of CRC but needs evidence from further studies.

Breast cancer is a heterogeneous disease for which the existence of monogenic and polygenic models of inheritance have been described for decades. Multigene panel testing is useful for the diagnosis of monogenic breast cancer predisposition, allowing to simultaneously sequence a large number of genes of several patients. However, this approach increases the identification of variants of unknown significance (VUS) that cannot be used in clinical decision-making. We first performed a systematic review and meta-analysis of studies conducting multigene panel testing on germline DNA of women with familial breast cancer. We found that using current panels, the probability of detecting a VUS is significantly higher than the probability of detecting a pathogenic variant. BRCA1 and BRCA2, the two most extensively studied breast cancer predisposing genes until now, were the only genes presenting the opposite trend. Reclassification of VUS in the other more recently identified genes is therefore required to drastically reduce the number of families for which genetic counselors are not able to draw a conclusion. Using a cohort of 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53 or CHEK2 mutation, we demonstrated that sequencing the matching tumor can help reclassify germline VUS based on second events hitting the same gene and provide clinically relevant information. We then explored the concept of oligogenic inheritance of familial breast cancer, and obtained data suggestive of the pertinence of this model. Analyzing the combined segregation patterns of low-frequency variants in affected familial relatives of 54 of our index patients, we found significantly higher segregation rates of rare variants in cancer-related genes in families in which affected members share a similar breast cancer phenotype, as compared to phenotypically heterogeneous families. Furthermore, cancer genes with disease-cosegregating variants harbored second, (MED - Sciences médicales) -- UCL, 2019

A cross-sectional, descriptive, unicentric and survey-type study was conducted in order to determine the characteristics of drug consumption in university students. 305 students, from the San Pedro University Center in Montes de Oca, San José, Costa Rica, were questioned. According to the data obtained, students invest mainly in the purchase of medicines when they get sick or feel bad (84.7%) and as a second reason (16.3%) to improve their concentration and increase energy. Sex influences this activity, due to the greater predisposition of drug use by women than in men, being the price the main factor that influences their purchase., Se realizó un estudio transversal, descriptivo, unicéntrico y de tipo encuesta para determinar las características del consumo de medicamentos en estudiantes universitarios. Fueron interrogados 305 estudiantes de un centro Universitario de San Pedro en Montes de Oca, San José, Costa Rica. Según los datos obtenidos, los estudiantes invierten principalmente en la compra de medicamentos cuando se enferman o se sienten mal (84,7%) y como una segunda razón (16,3%) para mejorar su concentración y aumentar su energía. El sexo influye en la actividad de compra de fármacos, debido a la mayor predisposición del consumo de medicamentos por parte de las mujeres que de los hombres, siendo el precio el principal factor que influye en su compra.

[ES] Las Neoplasias Mieloides Hereditarias consisten en un grupo de trastornos hematológicos de considerable incidencia y con una demostrada base genética, encontrándose una predisposición a su desarrollo en la herencia de alteraciones en línea germinal de diversos genes. Es por ello que se propone el desarrollo como técnica de diagnóstico, de un panel de genes dirigido, con la finalidad de poder detectar aquellas variantes heredadas que predisponen al desarrollo de este tipo de patología. El empleo de paneles genéticos hoy día se considera de mayor rentabilidad diagnóstica que los exomas dirigidos, ya que permite realizar diseños más manejables y donde se puedan tener en cuenta las características propias de los genes estudiados. Para el desarrollo del panel, se ha realizado un diseño custom, para lo cual se empezó por la realización de una revisión bibliográfica de los artículos relacionados con el tema para tratar de obtener la información más actual posible al respecto. Una vez seleccionados los genes diana, buscamos las regiones de interés de éstos -zonas exónicas, intrónicas situadas a +/- 10 nucleótidos, variantes de interés clínico situadas en regiones reguladoras... - a partir del manejo de la información extraída de diversas bases de datos, con el objetivo de acotar al máximo las regiones de interés, ya que el espacio que ofrecen los paneles custom es limitado. Una vez completado el diseño, es necesario validar la primera versión del panel de genes dirigido a través de diversos análisis que permitirán la obtención de datos, con el objetivo de establecer su sensibilidad y especificidad, utilizando para ello líneas celulares Coriell con variantes detectadas y validadas mediante distintas aproximaciones de secuenciación masiva, de manera que se consideran como patrones para la técnica de NGS (Next Generation Sequencing). El proceso de validación del panel es necesario antes de su empleo como herramienta diagnóstica., [EN] Hereditary Myeloid Neoplasms consist of a group of hematological disorders of considerable incidence and with a proven genetic base, finding a predisposition to their development in the inheritance of germline alterations of several genes. That is why we propose the development as a diagnostic technique, a directed gene panel, in order to detect those inherited variants that predispose to the development of this type of pathology. The use of genetic panels today is considered to be of greater diagnostic value than directed exomes, since it allows for more manageable designs and where the characteristics of the studied genes can be taken into account. For the panel development, a custom design has been made, for which a bibliographic review of the articles related to the subject was started in order to obtain the most up-to-date information possible. Once the target genes have been selected, we look for the regions of interest of these - exonic, intronic zones located at +/- 10 nucleotides, variants of clinical interest located in regulatory regions ... - from the handling of the information extracted from various databases , with the aim of limiting regions of interest to the maximum, since the space offered by custom panels is limited. Once the design is completed, it is necessary to validate the first version of the directed gene panel through various tests that will allow obtaining data, in order to establish its sensitivity and specificity, using Coriell cell lines with detected and validated variants using different approaches of massive sequencing, so that they are considered as standards for the NGS technique (Next Generation Sequencing). The validation process of the panel is necessary before its use as a diagnostic tool.

Central nervous system (CNS) tumors are the second most common type of cancer among children. Depending on histopathology, anatomic location, and genomic factors, specific subgroups of brain tumors have some of the highest cancer-related mortality rates or result in considerable lifelong morbidity. Pediatric CNS tumors often occur in patients with genetic predisposition, at times revealing underlying cancer predisposition syndromes. Advances in next-generation sequencing (NGS) have resulted in the identification of an increasing number of cancer predisposition genes. In this review, the literature on genetic predisposition to pediatric CNS tumors is evaluated with a discussion of potential future targets for NGS and clinical implications. Furthermore, we explore potential strategies for enhancing the understanding of genetic predisposition of pediatric CNS tumors, including evaluation of non-European populations, pan-genomic approaches, and large collaborative studies.

Background: Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European "Care for CMMRD"(C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment. Methods: Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017. Results: Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1-40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19-45) and 22% (95% CI: 12-37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families). Conclusions: Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: Canine breeds may be considered good animal models for the study of genetic predisposition to cancer, as they represent genetic clusters. From epidemiologic and case collection studies it emerges that some breeds are more likely to develop lymphoma or specific subtypes of lymphoma but available data are variable and geographically inconsistent. This study was born in the context of the European Canine Lymphoma Network with the aim of investigating the breed prevalence of canine lymphoma in different European countries and of investigating possible breed risk of lymphoma overall and/or different lymphoma subtypes.RESULTS: A total of 1529 canine nodal lymphoma cases and 55,529 control cases from 8 European countries/institutions were retrospectively collected. Odds ratios for lymphoma varied among different countries but Doberman, Rottweiler, boxer and Bernese mountain dogs showed a significant predisposition to lymphoma. In particular, boxers tended to develop T-cell lymphomas (either high- or low-grade) while Rottweilers had a high prevalence of B-cell lymphomas. Labradors were not predisposed to lymphoma overall but tended to develop mainly high-grade T-cell lymphomas. In contrast with previous studies outside of Europe, the European golden retriever population did not show any possible predisposition to lymphoma overall or to specific subtypes such as T-zone lymphoma.CONCLUSION: Further prospective studies with more precise and consistent subtype identification are needed to confirm our retrospective results and to create the basis for the investigation of possible genes involved in different predispositions.

Background Germline mutations of suppressor of fused homolog (SUFU) predispose to sonic hedgehog (SHH) medulloblastoma. Germline SUFU mutations have been reported in nevoid basal cell carcinoma syndrome (NBCCS), but little is known about the cancer risk and clinical spectrum. Methods We performed a retrospective review of all patients with medulloblastoma and a germline SUFU mutation in France. Results Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo). Macrocrania was present in 20 patients, but only 5 met the diagnostic criteria for NBCCS. Despite treatment with surgery and chemotherapy, to avoid radiotherapy in all patients except one, the outcome was worse than expected for SHH medulloblastoma, due to the high incidence of local relapses (8/22 patients) and second malignancies (n = 6 in 4/22 patients). The 5-year progression-free survival and overall survival rates were 42% and 66%. Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families. Medulloblastoma penetrance was incomplete, but higher than in Patched 1 (PTCH1) mutation carriers. Besides medulloblastoma, 19 other tumors were recorded among the 56 SUFU mutation carriers, including basal cell carcinoma (BCC) in 2 patients and meningioma in 3 patients. Conclusion Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma. The clinical spectrum differs between SUFU and PTCH1 mutation carriers, and BCC incidence is much lower in SUFU mutation carriers. The optimal treatment of SUFU mutation-associated medulloblastoma has not been defined., SCOPUS: re.j, info:eu-repo/semantics/published

Study Objectives: There is little information about familial aggregation of insomnia; however, this type of information is important to (1) improve our understanding of insomnia risk factors and (2) to design more effective treatment and prevention programs. This study aimed to investigate evidence of familial aggregation of insomnia among first-degree relatives of probands with and without insomnia. Methods: Cases (n = 134) and controls (n = 145) enrolled in a larger epidemiological study were solicited to invite their first-degree relatives and spouses to complete a standardized sleep/insomnia survey. In total, 371 first-degree relatives (Mage = 51.9 years, SD = 18.0; 34.3% male) and 138 spouses (Mage = 55.5 years, SD = 12.2; 68.1% male) completed the survey assessing the nature, severity, and frequency of sleep disturbances. The dependent variable was insomnia in first-degree relatives and spouses. Familial aggregation was claimed if the risk of insomnia was significantly higher in the exposed (relatives of cases) compared to the unexposed cohort (relatives of controls). The risk of insomnia was also compared between spouses in the exposed (spouses of cases) and unexposed cohort (spouses of controls). Results: The risk of insomnia in exposed and unexposed biological relatives was 18.6% and 10.4%, respectively, yielding a relative risk (RR) of 1.80 (p = .04) after controlling for age and sex. The risk of insomnia in exposed and unexposed spouses was 9.1% and 4.2%, respectively; however, corresponding RR of 2.13 (p = .28) did not differ significantly. Conclusions: Results demonstrate evidence of strong familial aggregation of insomnia. Additional research is warranted to further clarify and disentangle the relative contribution of genetic and environmental factors in insomnia.

Background: Thyroid cancer is a common malignant disease of the endocrine system with increasing incidence rates over the last few decades. In this study, we sought to analyze the possible association of 45 single nucleotide polymorphisms (SNPs) with thyroid cancer in a population from Rio Grande do Norte, Brazil. Methods: Based on histological analysis by a pathologist, 80 normal thyroid specimens of tissue adjacent to thyroid tumors were obtained from the biobank at the Laboratory of Pathology of Liga Norte Riograndense Contra o Câncer, Natal, RN. Patient samples were then genotyped using the MassARRAY platform (Sequenon, Inc) followed by statistical analysis employing the SNPassoc package in R program. The genotypic frequencies of all 45 SNPs obtained from the International HapMap Project database and based on data from the ancestral populations of European and African origin were used to compose the control study group. Results: In our study, the following 9 SNPs showed significant differences in their frequency when comparing the study and control groups: rs3744962, rs258107, rs1461855, rs4075022, rs9943744, rs4075570, rs2356508, rs17485896, and rs2651339. Furthermore, the SNPs rs374492 C/T and rs258107 C/T were associated with a relative risk for thyroid carcinoma of 3.78 (p= 6.27×10e−5) and 2.91 (p=8.27×10e−5), respectively, after Bonferroni’s correction for multiple comparisons. Conclusions: These nine polymorphisms could be potential biomarkers of predisposition to thyroid carcinoma in the population from Rio Grande do Norte. However, complementary studies including a control group with samples obtained from healthy subjects in Rio Grande do Norte state, should be conducted to confirm these results

Depression is a condition of a person feeling sad, disappointed when experiencing a change, loss, failure and becoming pathological when unable to adapt. Depression is a condition that affects a person affectively, physiologically, cognitively and behaviorally thus changing the usual patterns and responses. Major Depressive Disorder is a heterogeneous disease characterized by feelings of depression, anhedonia, changes in cognitive function, changes in sleep, changes in appetite, guilt that occur over two weeks, described with a loss of interest or pleasure in the usual activity and is a disease with neurobiological consequences involving structural, functional and molecular changes in some areas of the brain. Maladaptive neural responses, social, psychological, and physiological rejections interact with each other with other susceptibility factors, such as a history of depression, life stress levels, genetic factors, will increase a person's susceptibility to depression., Depresi adalah suatu kondisi seseorang merasa sedih, kecewa saat mengalami suatu perubahan, kehilangan, kegagalan dan menjadi patologis ketika tidak mampu beradaptasi. Depresi merupakan suatu keadaan yang mempengaruhi seseorang secara afektif, fisiologis, kognitif dan perilaku sehingga mengubah pola dan respon yang biasa dilakukan. Major Depressive Disorder merupakan penyakit heterogen ditandai dengan perasaan depresi, anhedonia, perubahan fungsi kognitif, perubahan tidur, perubahan nafsu makan, rasa bersalah yang terjadi selama dua minggu, digambarkan dengan hilangnya ketertarikan atau kesenangan akan aktivitas yang biasa dilakukan dan merupakan penyakit dengan konsekuensi neurobiologis yang melibatkan perubahan struktural, fungsional dan molekuler di beberapa daerah otak. Maladaptif respon saraf, penolakan sosial, psikologis, dan tingkat fisiologis berinteraksi satu sama lain dengan faktor kerentanan lainnya, seperti riwayat depresi, tingkat stres kehidupan, faktor genetik, akan meningkatkan kerentanan seseorang terhadap depresi.

Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence.

To study the functional role of the predisposed preference for Johansson's biological motion (BM) at an early stage of life, newly hatched domestic chicks, Gallus gallus domesticus, were exposed to a variety of motion pictures composed of light points (in red or yellow), and then tested for their learned colour preference. Point-light animations depicting the BM of a walking hen successfully facilitated both the approach activity during imprinting and the learned preference in the test, although significant positive correlations did not appear between these at the individual level. Furthermore, scrambling the light points did not significantly reduce the effects, whereas linear motion of a hen-shaped set of points had no effect. If pretreated with the linear motion, those chicks primed with a high BM preference score showed a high learning score in subsequent imprinting. We conclude that the local movement feature of the BM animation is critical in making chicks approach and learn the associated colour. We propose a scenario wherein naïve chicks have an innate preference for BM, which arises prior to imprinting through nonspecific visual experience in the early posthatch period. The induced BM preference then allows chicks to form a learned colour preference for the associated colour more effectively, leading to the development of tighter social attachment.

Violent offending and injecting drug use (IDU) are highly comorbid, serious behaviours. Despite extensive empirical investigation, the mechanisms underpinning this comorbidity remain unclear, which is, in part, due to a widespread assumption that drug use causes violence. In an effort to better understand the liability to violent offending among IDU, this thesis aimed to answer three major unresolved issues: (i) Does drug use cause violence or do underlying factors predispose individuals to drug use and violence? (ii) Is there heterogeneity in the nature of, and risk profiles for, violent offending? (iii) Are risks for violent offending specific to IDU? Addressing these issues was possible through quantitative examination of two large epidemiological datasets: one of community-based IDU (N=300) and a large treatment-based case-control sample (N=1,927). Analyses were structured according to a developmental framework that has not previously been used in this area. This framework focuses on the impact of early life predisposing factors on long term adverse behavioural outcomes. Violent offending was found to be highly prevalent among IDU, with a significant minority (approximately one-third) having committed a serious, injurious violent act. Findings regarding the risks for the likelihood (Chapter Two), severity (Chapter Three), stability (Chapter Four) and specificity (Chapter Five) of violent offending were remarkably consistent across the Chapters. Childhood psychopathology, higher scores on aggressive and impulsive trait measures, and childhood maltreatment were found to be strongly, positively correlated with the initial liability to violent offending. Substance use, on the other hand, appeared to play a greater role in the maintenance of violent behaviour. The findings further indicated that heterogeneity in violent patterns was best explained by the extent of cumulative exposure to early-life and substance use risks, such that IDU with greater early-life risk ex

Suicidal behavior constitutes a major public health problem. Based on the stress-diathesis model, biological correlates of a diathesis might help to predict risk after stressor-exposure. Structural changes in cortical and subcortical areas and their connections have increasingly been linked with the diathesis. The current study identified structural network changes associated with a diathesis using a whole-brain approach by examining the structural connectivity between regions in euthymic suicide attempters (SA). In addition, the association between connectivity measures, clinical and genetic characteristics was investigated. We hypothesized that SA showed lower connectivity strength, associated with an increased severity of general clinical characteristics and an elevated expression of short alleles in serotonin polymorphisms. Thirteen euthymic SA were compared with fifteen euthymic non-attempters and seventeen healthy controls (HC). Clinical characteristics and three serotonin-related genetic polymorphisms were assessed. Diffusion MRI together with anatomical scans were administered. Preprocessing was performed using Explore DTI. Whole brain tractography of the diffusion-weighted images was followed by a number of streamlines-weighted network analysis using NBS. The network analysis revealed decreased connectivity strength in SA in the connections between the left olfactory cortex and left anterior cingulate gyrus. Furthermore, SA had increased suicidal ideation, hopelessness and self-reported depression, but did not show any differences for the genetic polymorphisms. Finally, lower connectivity strength between the right calcarine fissure and the left middle occipital gyrus was associated with increased trait anxiety severity (rs = -0.78, p < 0.01) and hopelessness (rs = -0.76, p < 0.01). SA showed differences in white matter network connectivity strength associated with clinical characteristics. Together, these variables could play an important role in pre

The values of workers are determined by the cultural and social context that has influenced your development throughout your life, such as family, education, religion, work experience, formal, non-formal education, vision of work, scale values, which will create a particular perception towards administrative models.Although there is an emerging interest in relating these values with the study areas and business practice, this generates dilemmas and conflicts between individual and organizational objectives.The analyzed models assume an alignment of organizational values with the values of workers through their formal statements.It is important to consider the predisposition that workers have to share these organizational values, which is determined by the above personal history.This work aims to:Analyze the level of group willingness of workers to share organizational values.Analyze the level of individual predisposition of workers shared organizational values.This study is performed:No experimental: observe and analyze certain phenomena without the variables are handled.transectional: data are collected in a single moment to describe and analyze the variables with simultaneous measurement over time.For the investigation three companies according to their different approach and level of incorporation of values in their organizational statements were selected.To perform the analysis methodology "Associative Group Analysis" Noble and Deese, from studies by Diaz-Guerrero and Szalay (1993) is used., Los valores de los trabajadores están determinados por el contexto cultural-social que ha influido en su desarrollo a lo largo de su vida, como: familia, educación, religión, experiencia laboral, educación formal, educación no formal, visión del trabajo, escala de valores, los cuales le crean una percepción particular hacia los modelos administrativos.Aunque existe un incipiente interés por relacionar esos valores con las áreas de estudio y práctica empresariales, esto genera dilemas y conflictos entre los objetivos individuales y organizacionales.Los modelos analizados presumen una alineación de valores organizacionales con los valores de los trabajadores a través de sus declaraciones formales. Es importante considerar la predisposición que tengan los trabajadores para compartir esos valores organizacionales, la cual está determinada por los antecedentes personales antes mencionados.Este trabajo tiene como objetivo:Analizar el nivel de predisposición grupal de los trabajadores para compartir los valores organizacionales.Analizar el nivel de predisposición individual de los trabajadores para compartir los valores organizacionales.Para ello se realiza un estudio:No experimental: se observan y analizan ciertos fenómenos sin que se manipulen las variables.Transeccional: se recolectan datos en un solo momento para describir y analizar las variables con medición simultánea en el tiempo.Para la investigación se seleccionaron tres empresas de acuerdo a su diferente enfoque y nivel de incorporación de valores en sus declaraciones organizacionales.Para llevar a cabo el análisis se utiliza la metodología del “Análisis Asociativo de Grupo” de Noble y Deese, a partir de estudios realizados por Diaz-Guerrero y Szalay (1993).

In the Dutch population of Golden retrievers, a predisposition for the development of cancer in general and certain types of cancer (such as mast cell tumours and possibly also soft tissue sarcomas (STS)) was shown to exist. In addition, age, location and incidence of various tumours differed as related to the diagnostical procedure of choice, being either cytology or histology, indicating a selection bias for diagnostic procedure. A subset of the collected cohort, consisting of unclassified sarcomas, (n=110) were selected for revision. Revision was based on morphological characteristics and, if deemed necessary, additional immunohistochemistry. In 58 tumours, we were able to arrive at the diagnosis of a specific STS. As many as 31 tumours (28%), however, were on revision not considered to be STS. Four neoplasms (4%) were considered non-neoplastic. These numbers illustrate the necessity for revision (and \ possibly subclassification) of this group of tumours. DNA-aneuploidy may reflect a malignant nature of mesenchymal proliferations and herald gross genomic instability. Of all mesenchymal tumours examined within this study, half of all sarcomas were aneuploid. Benign mesenchymal neoplasms were rarely aneuploidy, and all of the inflammatory lesions were diploid. The determination of DNA ploidy status is considered to be of additional value when attempting to better differentiate between malignant and non-malignant mesenchymal lesions. In addition, hypoploidy appears more common in canine sarcomas and hyperploid cases show less deviation of the DNA index than human sarcomas. This strengthens the concept of interspecies variation in the evolution of gross chromosomal aberrations during cancer development. Aiming to identify genes causing the suspected breed predispositionfor the development of STS in both the Labrador- and Golden retriever breed,a genome-wide association study was performed. Results were suggestive for a germ-line genetic connection

Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated.

Plant activators are chemicals that induce disease resistance. The phytohormone salicylic acid (SA) is a crucial signal for systemic acquired resistance (SAR), and SA-mediated resistance is a target of several commercial plant activators, including Actigard (1,2,3-benzothiadiazole-7-thiocarboxylic acid-S-methyl-ester, BTH) and Tiadinil [N-(3-chloro-4-methylphenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, TDL]. BTH and TDL were examined for their impact on abscisic acid (ABA)-mediated, salt-induced disease predisposition in tomato seedlings. A brief episode of salt stress to roots significantly increased the severity of disease caused by Pseudomonas syringae pv. tomato (Pst) and Phytophthora capsici relative to non-stressed plants. Root treatment with TDL induced resistance to Pst in leaves and provided protection in both non-stressed and salt-stressed seedlings in wild-type and highly susceptible NahG plants. Non-stressed and salt-stressed ABA-deficient sitiens mutants were highly resistant to Pst. Neither TDL nor BTH induced resistance to root infection by Phytophthora capsici, nor did they moderate the salt-induced increment in disease severity. Root treatment with these plant activators increased the levels of ABA in roots and shoots similar to levels observed in salt-stressed plants. The results indicate that SAR activators can protect tomato plants from bacterial speck disease under predisposing salt stress, and suggest that some SA-mediated defense responses function sufficiently in plants with elevated levels of ABA.

Currently, the link between university and society can be articulated through the usual channels (OTRIs, Foundations and UniversityIndustry Chairs, Spinoffs, placements ...) and through other resources such as online social networks. In the field of research and teaching, these networks have become an interesting tool for building learning communities (Santamaria, 2008). Moreover, as we propose in our work, social networks can serve as a bridge between the academic and professional, encouraging communication, collaboration, networking and management and knowledge transfer between the two areas. The objective of this research is to know and appreciate the willingness of teachers, students and professionals to use an academicprofessional social networking., Actualmente, el vínculo entre Universidad y sociedad puede articularse tanto a través de los canales habituales (OTRIs, Fundaciones y Cátedras UniversidadEmpresa, Spinoffs, prácticas en empresas…) como por medio de otros recursos como las redes sociales en Internet. En el ámbito de la investigación y la docencia, dichas redes se han convertido en una interesante herramienta para la construcción de comunidades de aprendizaje (Santamaría, 2008). Además, como proponemos en nuestro trabajo, pueden servir como nexo entre el mundo académico y profesional, favoreciendo la comunicación, la colaboración, el networking y la gestión y transferencia de conocimiento entre ambos. El objetivo de la presente investigación es la de conocer y valorar la predisposición de docentes, estudiantes y profesionales al uso de redes sociales de carácter académicoprofesional.

Clinicians referring patients for genetic testing for Lynch syndrome will sooner or later receive results for DNA Mismatch Repair (MMR) genes reporting DNA changes that are unclear from a clinical point of view. These changes are referred to as variants of unknown, or unclear, clinical significance (VUS). In contrast to clearly pathogenic mutations, VUS do not firmly diagnose Lynch syndrome at the molecular level and cannot be used to identify with certainty any of the patients' asymptomatic relatives as Lynch syndrome mutation carriers. The International database that collects MMR gene variants (www.insight-group.org/mutations) already lists more than 1,000 different VUSs and these variants are likely the tip of the iceberg. This paper aims at introducing non-geneticist clinicians to the topic of clinical MMR gene variant interpretation. Many lines of evidence are being used to classify VUS. Some are already familiar to clinicians and others may be less familiar but are expected to become important in clinical genetics in the coming years. Clinicians can play an important role in collecting the data needed to interpret the MMR variants detected in their patients.

El interés, la habilidad o la actitud positiva hacia algo nos suele facilitar el aprendizaje en esa área o materia. En esta línea estudiamos si a través de la Educación Física se podían adquirir actitudes o valores relacionados con el cuidado del medio natural. Así quisimos comprobar si la predisposición o el interés por la materia de Educación Física resultaba facilitador de la adquisición de valores relacionados con el medio ambiente. Desarrollamos un programa de Educación Física (de actividades en el medio natural) y Educación Ambiental y valoramos si el interés o actitud positiva hacia la Educación Física aportaba beneficios en el desarrollo de conductas conservacionistas hacia el medio ambiente., Interest, skill or positive attitude in a subject makes us easier learning something of it. In this way, we studied if through Physical Education people could get attitudes or values about environment. We wanted to know if the predisposition to Physical Education makes easy the acquisition of environmental values. We developed a program about Physical Activities in Nature and Environmental Education and we studied if this predisposition brings profits about the development of conservationist conducts towards the environment.

Diaphanospondylodysostosis (DSD) is a rare skeletal dysplasia syndrome resulting from disordered mesenchymal differentiation. Children with DSD generally die in utero or during the first month of life from severe thoracic insufficiency syndrome. An association of DSD with nephroblastomatosis has been observed, but the natural history of such nephroblastomatosis remains poorly characterized due to the rarity of the underlying condition. We describe a patient with DSD who developed bilateral hyperplastic nephroblastomatosis that ultimately evolved into therapy-resistant anaplastic Wilms tumor (nephroblastoma).

Oral squamous cell carcinomas (OSCCs) are associated with poor prognosis, and despite advances in therapy approaches, no major improvement in survival has been achieved in the recent years. Efforts are now directed toward finding new biological markers that could predict tumor behavior more accurately. OSCCs, as the majority of malignant tumors, arise from progressive accumulation of genetic and epigenetic lesions, transforming normal cells into malignant. In this paper, an analysis of current studies directed to understanding the underlying mechanisms of OSCC pathogenesis was presented. The emphasis was put on mutational analysis of cancer genes, as well as on the role of viral infections and methylation processes in OSCC. Finally, an overview of studies that tried to determine the possibility for developing OSCC was given., Oralne skvamocelularne karcinome (OSCK) odlikuje uglavnom loša prognoza i, uprkos pomacima u terapijskim postupcima, poslednjih godina nije ostvaren napredak u preživljavanju osoba s ovim tumorom. Velike nade se polažu u molekularnu medicinu i pronalaženje novih bioloških markera pomoću kojih bi preciznije nego što to dopuštaju klinički i histopatološki parametri moglo da se predvidi ponašanje tumora. OSCK, kao i većina drugih malignih oboljenja, rezultat su postupne akumulacije raznovrsnih genetičkih i epigenetičkih promena u ćelijama, koje od normalnih postaju neoplastične. U ovom radu dat je presek nekih od pravaca istraživanja na polju molekularne biologije oralnih karcinoma, s osvrtom na studije koje se bave ispitivanjem somatskih mutacija u kancerskim genima, učešćem onkogenih virusa u patogenezi i značaju procesa metilacije za OSCK. Takođe su pomenute studije posvećene utvrđivanju eventualnog postojanja predispozicije za razvoj OSCK.

SCOPUS: ar.j, info:eu-repo/semantics/published

The parasite Neospora caninum is an intracellular protozoa discovered in the late 1980s. N. caninum has an indirect lifecycle which means it needs a definitive host and an intermediate host. The confirmed definitive host for N. caninum is dog and the intermediate hosts are among others dog and cattle. The parasite has been found in many parts of the world and is an important cause of abortion in cattle and severe disease in dogs. Young dogs often develop hind limp paralysis as the main symptom, while middle-aged and older dogs often develop more diffuse symptoms as ataxia, pneumonia and dermatitis. In today’s literature the discussion is divided into two opinions whether the difference in symptoms depends on the age of the dog or the status of the immune system. There also seems to be a breed predisposition to the disease since most of the reported cases concerns three breeds; Boxer, Labrador retriever and Greyhound. This review describes the different symptoms and clinical findings found in dogs infected with N. caninum. Furthermore, the theories whether the age and breed of a dog can determine the symptoms after an infection caused by N. caninum, are discussed.

BACKGROUND: Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS: We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS: Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS: Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate (c) 2010 Wiley-Liss, Inc.

Business graduates leave university equipped with core skills necessary to succeed in their chosen environment. One of these is an ethical perspective. Financial institutions and accounting firms are the major employers of business graduates. They assume a basic understanding of concepts when designing training for their new employees. However, business graduates are not a homogeneous group and this study examines whether the ethical sensitivities of graduates can differ depending upon their business major selected. Two groups of final year business students (270 in total), one majoring in accounting (Acc), 155 students, one in banking and finance (B&F), 115 students, were selected and their ethical attitudes tested by way of business vignettes. Even though they had received the same level of ethics training in their course, significant differences were discovered. Both individually, and when formed into groups (Acc 58 groups, B&F 57 groups), accounting majors appeared more ethical than their B&F counterparts. Also, as a cohort, accounting majors offered significantly more consistent responses. The B&F students appeared a more disparate group. As instruction level was the same, irrespective of major selected, it would appear the groups are predisposed to differing ethical attitudes to business dilemmas. The implications of this study are crucial for academics and perspective employers. Ethical training at all levels needs to be tailored specifically to the group being instructed. A standardised model of ethics training for all business students may not be effective.

Locus-specific databases (LSDBs) are curated collections of sequence variants in genes associated with disease. LSDBs of cancer-related genes often serve as a critical resource to researchers, diagnostic laboratories, clinicians, and others in the cancer genetics community. LSDBs are poised to play an important role in disseminating clinical classification of variants. The IARC Working Group on Unclassified Genetic Variants has proposed a new system of five classes of variants in cancer susceptibility genes. However, standards are lacking for reporting and analyzing the multiple data types that assist in classifying variants. By adhering to standards of transparency and consistency in the curation and annotation of data, LSDBs can be critical for organizing our understanding of how genetic variation relates to disease. In this article we discuss how LSDBs can accomplish these goals, using existing databases for BRCA1, BRCA2, MSH2, MLH1, TP53, and CDKN2A to illustrate the progress and remaining challenges in this field. We recommend that: 1) LSDBs should only report a conclusion related to pathogenicity if a consensus has been reached by an expert panel. 2) The system used to classify variants should be standardized. The Working Group encourages use of the five class system described in this issue by Plon and colleagues. 3) Evidence that supports a conclusion should be reported in the database, including sources and criteria used for assignment. 4) Variants should only be classified as pathogenic if more than one type of evidence has been considered. 5) All instances of all variants should be recorded. Hum Mutat 29(11), 1273-1281, 2008. Published 2008 Wiley-Liss, Inc.