Value of Prostate-Specific Antigen Kinetics in Patients with Low-Risk Prostate Cancer under Active Surveillance.

INTRODUCTION: This study analyzes the value of PSA kinetics, PSA speed (vPSA), and PSA doubling time (PSAdt), in patients with low-risk prostate cancer who are in an active surveillance (AS) program. METHODS: An observational, retrospective, and longitudinal study of a sample of 86 patients included in AS program between January 2014 and October 2021 was conducted. A review of their medical records was performed, and PSA kinetics were calculated, analyzing the causes of discontinuation of the AS program and its relationship with PSA kinetics. RESULTS: The mean age was 63.39 years, and the median follow-up was 62.55 months. The mean PSA at diagnosis was 8.27 ng/mL. A median of PSAdt of 62.55 months and 1.3 ng/mL/year for vPSA was obtained. 35 patients left the program, with a higher percentage of patients leaving with a PSAdt less than 36 months (73.7 vs. 31.1%) and a vPSA greater than 2 ng/mL/year (68.2 vs. 31.3%). The probability of permanence and the time of permanence in AS were statistically significantly higher for those patients with favorable kinetic parameters. CONCLUSION: PSA kinetics is a parameter to take into account when making decisions to keep patients in an AS program.

Assessment of the treatment needs of community recovery Services in Spain: From the perspective of service users, families, and mental health professionals.

Profile of Community Recovery Services users has changed over the years and has become more diverse. To explore the evolution of treatment needs, this study aimed to identify users' needs, from the point of view of different agents implicated in the recovery process. We explored the consistency between the agents using the focus group technique. We defined four groups (n = 58): service users, family members, professionals, and referring professionals. We pre-identified topics related to recovery, such as illness-related losses, imaginary of CRS, expectations, activities, and life goals. All agents recognised losses related to the mental illness, the need for carrying activities out of the Community Recovery Services, and for including families in the recovery process. The groups differed in some areas, such as the identification of activities that should be encouraged, or the importance of promoting vital expectations. Our findings suggest that it is important to identify the needs of different agents involved in the recovery process. There is consistency in the service users' needs, but there are some differences that need to be considered. Interventions should be personalised, covering functional, cognitive, and relational losses related to the mental illness.

Genomic architecture and functional effects of potential human inversion supergenes.

Supergenes are involved in adaptation in multiple organisms, but they are little known in humans. Genomic inversions are the most common mechanism of supergene generation and maintenance. Here, we review the information about two large inversions that are the best examples of potential human supergenes. In addition, we do an integrative analysis of the newest data to understand better their functional effects and underlying genetic changes. We have found that the highly divergent haplotypes of the 17q21.31 inversion of approximately 1.5 Mb have multiple phenotypic associations, with consistent effects in brain-related traits, red and white blood cells, lung function, male and female characteristics and disease risk. By combining gene expression and nucleotide variation data, we also analysed the molecular differences between haplotypes, including gene duplications, amino acid substitutions and regulatory changes, and identify CRHR1, KANLS1 and MAPT as good candidates to be responsible for these phenotypes. The situation is more complex for the 8p23.1 inversion, where there is no clear genetic differentiation. However, the inversion is associated with several related phenotypes and gene expression differences that could be linked to haplotypes specific of one orientation. Our work, therefore, contributes to the characterization of both exceptional variants and illustrates the important role of inversions. This article is part of the theme issue 'Genomic architecture of supergenes: causes and evolutionary consequences'.

GCAT|Panel, a comprehensive structural variant haplotype map of the Iberian population from high-coverage whole-genome sequencing.

The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization, and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression Models (LRMs), we present a catalogue of 35 431 441 variants, including 89 178 SVs (≥50 bp), 30 325 064 SNVs and 5 017 199 indels, across 785 Illumina high coverage (30x) whole-genomes from the Iberian GCAT Cohort, containing a median of 3.52M SNVs, 606 336 indels and 6393 SVs per individual. The haplotype panel is able to impute up to 14 360 728 SNVs/indels and 23 179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with Mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies.

Factores que influyen en la elección de la especialidad de Medicina Familiar y Comunitaria / Elements influencing the election of Family and Community Medicine

Objetivo: Analizar las percepciones, motivaciones y razones que influyen al elegir la especialidad de Medicina Familiar y Comunitaria (MFyC), y explorar posibles propuestas de cambio sobre el modelo sanitario y la formación universitaria. Diseño: Estudio cualitativo descriptivo-interpretativo de perspectiva socioconstructivista. Emplazamiento: Unidades docentes del Área Metropolitana de Barcelona. Participantes y contexto: Se contactó con 55 residentes de primer año de MFyC pertenecientes a la U.D. MFyC Barcelona Ciutat ICS vía telefónica, y se reclutaron 25 participantes que fueron segmentadas en dos grupos según hubieran escogido MFyC como primera opción o no. Mediante muestreo en bola de nieve, se reclutaron once residentes de primer año de otras especialidades. Método: Constitución de tres grupos focales: (a) MFyC como primera opción, (b) no como primera opción y (c) otras especialidades. Desarrollo de entrevistas grupales semiestructuradas de dos horas de duración. Codificación inductiva con una primera triangulación intra-grupo y una segunda triangulación inter-grupo, posterior análisis de contenido temático. Resultados: La elección de plaza MIR representa un gran hito académico y es pensado como determinante para el futuro tanto profesional como personal. Así, se dibuja como resultado de una compleja trama de elementos influyentes, destacando la formación universitaria, el modelo sanitario, las expectativas laborales y la valoración social de la especialidad. Poniendo en relación los diferentes factores, se pone de manifiesto el fenómeno llamado desprestigio de la AP. Conclusión: La especialidad de MFyC no será atractiva en un sistema sanitario y formativo hospitalo-céntrico que no apuesta por la AP organizativa ni económicamente.(AU)

Aim: To analyze the perceptions, motives and reasons that influence the election of Family and Community Medicine (FCM) speciality, thus exploring possible proposals for change in the health system model and university training. Design: Descriptive–interpretative qualitative research from a socio-constructivist perspective. Emplacement: Medical speciality training departments in the Metropolitan Area of Barcelona. Participants and context: 55 first year junior doctors belonging to the FCM Barcelona Ciutat ICS training department were contacted; 25 agreed to participate. They were segmented into two groups depending on if the choice of FCM had been their first option or not. Through snowball sampling 11 more junior doctors from other specialities were recruited. Method: Three focus groups were formed: (a) first choice FCM, (b) not first choice FCM and (c) other specialities. Semi-structured 2-h long interviews took place with each of the groups. Literal transcription and inductive codification with a first triangulation within each group and a second one between the three of them and thematic content analyses. Results: The choice of speciality is lived as an academic milestone and is thought determining professional and personally. It is a complex weave of influencing elements but some of main factors were university training, health system model, professional prospects and the social appreciation of the speciality. Analyzing the relation between these elements puts light on a phenomena we have called “the discredit of Primary Care (PC)”. Conclusion: The FCM specialty will not be attractive in a hospital-centric health and training system that does not bet on PC organizationally or economically.(AU)

[Elements influencing the election of Family and Community Medicine]. / Factores que influyen en la elección de la especialidad de Medicina Familiar y Comunitaria.

AIM: To analyze the perceptions, motives and reasons that influence the election of Family and Community Medicine (FCM) speciality, thus exploring possible proposals for change in the health system model and university training. DESIGN: Descriptive-interpretative qualitative research from a socio-constructivist perspective. EMPLACEMENT: Medical speciality training departments in the Metropolitan Area of Barcelona. PARTICIPANTS AND CONTEXT: 55 first year junior doctors belonging to the FCM Barcelona Ciutat ICS training department were contacted; 25 agreed to participate. They were segmented into two groups depending on if the choice of FCM had been their first option or not. Through snowball sampling 11 more junior doctors from other specialities were recruited. METHOD: Three focus groups were formed: (a) first choice FCM, (b) not first choice FCM and (c) other specialities. Semi-structured 2-h long interviews took place with each of the groups. Literal transcription and inductive codification with a first triangulation within each group and a second one between the three of them and thematic content analyses. RESULTS: The choice of speciality is lived as an academic milestone and is thought determining professional and personally. It is a complex weave of influencing elements but some of main factors were university training, health system model, professional prospects and the social appreciation of the speciality. Analyzing the relation between these elements puts light on a phenomena we have called "the discredit of Primary Care (PC)". CONCLUSION: The FCM specialty will not be attractive in a hospital-centric health and training system that does not bet on PC organizationally or economically.

Single-cell strand sequencing of a macaque genome reveals multiple nested inversions and breakpoint reuse during primate evolution.

Rhesus macaque is an Old World monkey that shared a common ancestor with human ∼25 Myr ago and is an important animal model for human disease studies. A deep understanding of its genetics is therefore required for both biomedical and evolutionary studies. Among structural variants, inversions represent a driving force in speciation and play an important role in disease predisposition. Here we generated a genome-wide map of inversions between human and macaque, combining single-cell strand sequencing with cytogenetics. We identified 375 total inversions between 859 bp and 92 Mbp, increasing by eightfold the number of previously reported inversions. Among these, 19 inversions flanked by segmental duplications overlap with recurrent copy number variants associated with neurocognitive disorders. Evolutionary analyses show that in 17 out of 19 cases, the Hominidae orientation of these disease-associated regions is always derived. This suggests that duplicated sequences likely played a fundamental role in generating inversions in humans and great apes, creating architectures that nowadays predispose these regions to disease-associated genetic instability. Finally, we identified 861 genes mapping at 156 inversions breakpoints, with some showing evidence of differential expression in human and macaque cell lines, thus highlighting candidates that might have contributed to the evolution of species-specific features. This study depicts the most accurate fine-scale map of inversions between human and macaque using a two-pronged integrative approach, such as single-cell strand sequencing and cytogenetics, and represents a valuable resource toward understanding of the biology and evolution of primate species.

Determining the impact of uncharacterized inversions in the human genome by droplet digital PCR.

Despite the interest in characterizing genomic variation, the presence of large repeats at the breakpoints hinders the analysis of many structural variants. This is especially problematic for inversions, since there is typically no gain or loss of DNA. Here, we tested novel linkage-based droplet digital PCR (ddPCR) assays to study 20 inversions ranging from 3.1 to 742 kb flanked by inverted repeats (IRs) up to 134 kb long. Of those, we validated 13 inversions predicted by different genome-wide techniques. In addition, we obtained new experimental human population information across 95 African, European, and East Asian individuals for 16 inversions, including four already validated variants without high-throughput genotyping methods. Through comparison with previous data, independent replicates and both inversion breakpoints, we demonstrate that the technique is highly accurate and reproducible. Most studied inversions are widespread across continents, and their frequency is negatively correlated with genetic length. Moreover, all except two show clear signs of being recurrent, and we could better define the factors affecting recurrence levels and estimate the inversion rate across the genome. Finally, the generated genotypes have allowed us to check inversion functional effects, validating gene expression differences reported before for two inversions and finding new candidate associations. Therefore, the developed methodology makes it possible to screen these and other complex genomic variants quickly in a large number of samples for the first time, highlighting the importance of direct genotyping to assess their potential consequences and clinical implications.

Comprehensive management of obstructive sleep apnea by telemedicine: Clinical improvement and cost-effectiveness of a Virtual Sleep Unit. A randomized controlled trial.

INTRODUCTION: Obstructive sleep apnea (OSA) is a prevalent disease associated with significant morbidity and high healthcare costs. Information and communication technology could offer cost-effective management options. OBJECTIVES: To evaluate an out-of-hospital Virtual Sleep Unit (VSU) based on telemedicine to manage all patients with suspected OSA, including those with and without continuous positive airway pressure (CPAP) therapy. METHODS: This was an open randomized controlled trial. Patients with suspected OSA were randomized to hospital routine (HR) or VSU groups to compare the clinical improvement and cost-effectiveness in a non-inferiority analysis. Improvement was assessed by changes in the Quebec Sleep Questionnaire (QSQ), EuroQol (EQ-5D and EQ-VAS), and Epworth Sleepiness Scale (ESS). The follow-up was 3 months. Cost-effectiveness was assessed by a Bayesian analysis based on quality-adjusted life-years (QALYs). RESULTS: The HR group (n: 92; 78% OSA, 57% CPAP) compared with the VSU group (n: 94; 83% OSA, 43% CPAP) showed: CPAP compliance was similar in both groups, the QSQ social interactions domain improved significantly more in the HR group whereas the EQ-VAS improved more in the VSU group. Total and OSA-related costs were lower in the VSU group than the HR. The Bayesian cost-effectiveness analysis showed that VSU was cost-effective for a wide range of willingness to pay for QALYs. CONCLUSIONS: The VSU offered a cost-effective means of improving QALYs than HR. However, the assessment of its clinical improvement was influenced by the choice of the questionnaire; hence, additional measurements of clinical improvement are needed. Our findings indicate that VSU could help with the management of many patients, irrespective of CPAP use.

Evolutionary and functional impact of common polymorphic inversions in the human genome.

Inversions are one type of structural variants linked to phenotypic differences and adaptation in multiple organisms. However, there is still very little information about polymorphic inversions in the human genome due to the difficulty of their detection. Here, we develop a new high-throughput genotyping method based on probe hybridization and amplification, and we perform a complete study of 45 common human inversions of 0.1-415 kb. Most inversions promoted by homologous recombination occur recurrently in humans and great apes and they are not tagged by SNPs. Furthermore, there is an enrichment of inversions showing signatures of positive or balancing selection, diverse functional effects, such as gene disruption and gene-expression changes, or association with phenotypic traits. Therefore, our results indicate that the genome is more dynamic than previously thought and that human inversions have important functional and evolutionary consequences, making possible to determine for the first time their contribution to complex traits.

Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-ß1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt.

Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and TGF-ß1 cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from IPF patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide (PAA) gels. We found that TGF-ß1 consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the FAK/Akt pathway, whereas FAK depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and TGF-ß1 that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by TGF-ß1 alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger FAK and Akt activities in the former cells. These findings provide new insights on how matrix stiffening and TGF-ß1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation.

A phase Ib trial of continuous once-daily oral afatinib plus sirolimus in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer and/or disease progression following prior erlotinib or gefitinib.

OBJECTIVES: Dysregulation of the downstream PI3K/AKT/mTOR signaling pathway is a proposed mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We investigated safety and antitumor activity of afatinib plus sirolimus as a potential combination to reverse acquired resistance to EGFR-TKIs in a phase IB trial in patients with EGFR mutation-positive non-small-cell lung cancer (EGFR mut NSCLC) and/or disease progression following prior erlotinib/gefitinib. MATERIALS AND METHODS: Patients with EGFR mut NSCLC and/or disease progression following at least prior erlotinib/gefitinib were included in the trial. The primary endpoint was incidence of dose-limiting toxicities (DLT) to determine the maximum tolerated dose (MTD). Four initial dose cohorts were proposed to evaluate DLTs. Other endpoints included tumor response, safety, progression-free survival (PFS) and pharmacokinetics. RESULTS: Thirty-nine patients received afatinib and sirolimus. Additional dose cohorts were added since the second cohort (afatinib 40mg/day and sirolimus 5mg/day) was considered to have excessive toxicity. All patients experienced adverse events (AE) [grade 3: 66.7%; serious AE: 56.4%]. The most frequent AEs were diarrhea (94.9%), mucosal inflammation (64.1%), asthenia (53.8%) and rash (53.8%). Discontinuations and dose reduction due to AEs occurred in 23.1% and 25.6% of patients. MTD was determined as afatinib 30mg and sirolimus 1mg. Responses were observed in 5 patients (12.8%) [2 (5.1%) with confirmed partial response (PR); 3 (7.7%) with unconfirmed PR], and stable disease in 18 patients (46.2%). Four of the 5 responses were at doses above MTD. PFS at 6 months was estimated in 33.3% (median PFS 3.4 months). Pharmacokinetic parameters of afatinib and sirolimus were similar after single administration or in combination. CONCLUSION: The combination of afatinib and sirolimus showed lower responses than expected. Together with increased AEs and poor tolerability, this precludes clinical use and further clinical development of this combination. No pharmacokinetic interactions were observed. CLINICALTRIALS. GOV IDENTIFIER: NCT00993499.

The antigen-binding fragment of human gamma immunoglobulin prevents amyloid ß-peptide folding into ß-sheet to form oligomers.

The amyloid beta-peptide (Aß) plays a leading role in Alzheimer's disease (AD) physiopathology. Even though monomeric forms of Aß are harmless to cells, Aß can aggregate into ß-sheet oligomers and fibrils, which are both neurotoxic. Therefore, one of the main therapeutic approaches to cure or delay AD onset and progression is targeting Aß aggregation. In the present study, we show that a pool of human gamma immunoglobulins (IgG) protected cortical neurons from the challenge with Aß oligomers, as assayed by MTT reduction, caspase-3 activation and cytoskeleton integrity. In addition, we report the inhibitory effect of IgG on Aß aggregation, as shown by Thioflavin T assay, size exclusion chromatography and atomic force microscopy. Similar results were obtained with Palivizumab, a human anti-sincitial virus antibody. In order to dissect the important domains, we cleaved the pool of human IgG with papain to obtain Fab and Fc fragments. Using these cleaved fragments, we functionally identified Fab as the immunoglobulin fragment inhibiting Aß aggregation, a result that was further confirmed by an in silico structural model. Interestingly, bioinformatic tools show a highly conserved structure able to bind amyloid in the Fab region. Overall, our data strongly support the inhibitory effect of human IgG on Aß aggregation and its neuroprotective role.

Detailed analysis of inversions predicted between two human genomes: errors, real polymorphisms, and their origin and population distribution.

The growing catalogue of structural variants in humans often overlooks inversions as one of the most difficult types of variation to study, even though they affect phenotypic traits in diverse organisms. Here, we have analysed in detail 90 inversions predicted from the comparison of two independently assembled human genomes: the reference genome (NCBI36/HG18) and HuRef. Surprisingly, we found that two thirds of these predictions (62) represent errors either in assembly comparison or in one of the assemblies, including 27 misassembled regions in HG18. Next, we validated 22 of the remaining 28 potential polymorphic inversions using different PCR techniques and characterized their breakpoints and ancestral state. In addition, we determined experimentally the derived allele frequency in Europeans for 17 inversions (DAF = 0.01-0.80), as well as the distribution in 14 worldwide populations for 12 of them based on the 1000 Genomes Project data. Among the validated inversions, nine have inverted repeats (IRs) at their breakpoints, and two show nucleotide variation patterns consistent with a recurrent origin. Conversely, inversions without IRs have a unique origin and almost all of them show deletions or insertions at the breakpoints in the derived allele mediated by microhomology sequences, which highlights the importance of mechanisms like FoSTeS/MMBIR in the generation of complex rearrangements in the human genome. Finally, we found several inversions located within genes and at least one candidate to be positively selected in Africa. Thus, our study emphasizes the importance of careful analysis and validation of large-scale genomic predictions to extract reliable biological conclusions.

Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung.

Senescence in cancer cells acts as a tumor suppressor, whereas in fibroblasts enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of cancer subtypes. However, the presence of senescent TAFs in lung cancer remains undefined. We examined senescence in TAFs from primary lung cancer and paired control fibroblasts from unaffected tissue in three major histologic subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Three independent senescence markers (senescence-associated beta-galactosidase, permanent growth arrest and spreading) were consistently observed in cultured LCC-TAFs only, revealing a selective premature senescence. Intriguingly, SCC-TAFs exhibited a poor growth response in the absence of senescence markers, indicating a dysfunctional phenotype rather than senescence. Co-culturing normal fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to render fibroblasts senescent through oxidative stress, indicating that senescence in LCC-TAFs is driven by heterotypic signaling. In addition, senescent fibroblasts provided selective growth and invasive advantages to LCC cells in culture compared to normal fibroblasts. Likewise, senescent fibroblasts enhanced tumor growth and lung dissemination of tumor cells when co-injected with LCC cells in nude mice beyond the effects induced by control fibroblasts. These results define the subtype-specific aberrant phenotypes of lung TAFs, thereby challenging the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless of their subtype. Importantly, because LCC often distinguishes itself in the clinic by its aggressive nature, we argue that senescent TAFs may contribute to the selective aggressive behavior of LCC tumors.

Spanish version of the link´s perceived devaluaton and discrimination scale / Versión española de la escala Perceived Devaluation and Discrimination de Link

BACKGROUND: The aim of this study is to translate, adapt and validate the «Perceived Devaluation and Discrimination Scale» (PDD) in Spanish in a sample of people with schizophrenia. METHOD: A total of 130 people between 18 and 65 years and with a diagnosis of schizophrenia according to DSM-IV-R criteria from Barcelona and Vitoria were included. The patients were assessed with the translated version of the PDD, the Social Functioning Scale (SFS), the Global Assessment of Functioning (GAF), the Clinical Global Impression Scale (CGI-S) and the Self-perception of Stigma Questionnaire for people with schizophrenia (SSQ). RESULTS: The questionnaire scored a Cronbach's a of .868 regarding its internal consistency reliability. Two components were found in the factorial analysis explaining 40% of the variance of the instrument (component 1 associated with individual self-perception and component 2 refers more to social stigma). The stability of the instrument measured using the intraclass correlation coefficient on both occasions oscillated between .415 and .806. Significant correlations were found with SSQ and SFS. CONCLUSIONS: The Spanish version of the PDD seems a good instrument for the assessment of self stigma

ANTECEDENTES: el objetivo de este estudio es traducir, adaptar y validar la «Perceived Devaluation and Discrimination Scale» (PDD) en español en una muestra de personas con esquizofrenia. MÉTODO: se incluyeron un total de 130 personas de entre 18 y 65 años con un diagnóstico de esquizofrenia según los criterios del DSM-IV-R de Barcelona y Vitoria. Los pacientes fueron evaluados con la versión traducida de la PDD, la Escala de Funcionamiento Social (SFS), la Evaluación Global de Funcionamiento (GAF), la escala Clinical Global Impresión (CGI-S) y la autopercepción de Estigma Cuestionario para las personas con esquizofrenia (SSQ). RESULTADOS: la consistencia interna del cuestionario, evaluada utilizando a de Cronbach, fue .868. Dos componentes fueron encontrados en el análisis factorial explicando el 40% de la varianza del instrumento (componente 1 asociado a la auto-percepción y el componente 2 individual se refiere más al estigma social). Los valores de estabilidad temporal medidos utilizando el coeficiente de correlación intraclase en ambas ocasiones oscilan entre .415 y .806. Se encontraron correlaciones significativas con SSQ y SFS. CONCLUSIONES: la versión española de PDD parece un buen instrumento para la evaluación del auto-estigma

Spanish version of the Link's Perceived Devaluation and Discrimination scale.

BACKGROUND: The aim of this study is to translate, adapt and validate the “Perceived Devaluation and Discrimination Scale” (PDD) in Spanish in a sample of people with schizophrenia. METHOD: A total of 130 people between 18 and 65 years and with a diagnosis of schizophrenia according to DSM-IV-R criteria from Barcelona and Vitoria were included. The patients were assessed with the translated version of the PDD, the Social Functioning Scale (SFS), the Global Assessment of Functioning (GAF), the Clinical Global Impression Scale (CGI-S) and the Self-perception of Stigma Questionnaire for people with schizophrenia (SSQ). RESULTS: The questionnaire scored a Cronbach’s a of .868 regarding its internal consistency reliability. Two components were found in the factorial analysis explaining 40% of the variance of the instrument (component 1 associated with individual self-perception and component 2 refers more to social stigma). The stability of the instrument   measured using the intraclass correlation coefficient on both occasions oscillated between .415 and .806. Significant correlations were found with SSQ and SFS. CONCLUSIONS: The Spanish version of the PDD seems a good instrument for the assessment of self stigma.

Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts.

Epigenetic changes through altered DNA methylation have been implicated in critical aspects of tumor progression, and have been extensively studied in a variety of cancer types. In contrast, our current knowledge of the aberrant genomic DNA methylation in tumor-associated fibroblasts (TAFs) or other stromal cells that act as critical coconspirators of tumor progression is very scarce. To address this gap of knowledge, we conducted genome-wide DNA methylation profiling on lung TAFs and paired control fibroblasts (CFs) from non-small cell lung cancer patients using the HumanMethylation450 microarray. We found widespread DNA hypomethylation concomitant with focal gain of DNA methylation in TAFs compared to CFs. The aberrant DNA methylation landscape of TAFs had a global impact on gene expression and a selective impact on the TGF-ß pathway. The latter included promoter hypermethylation-associated SMAD3 silencing, which was associated with hyperresponsiveness to exogenous TGF-ß1 in terms of contractility and extracellular matrix deposition. In turn, activation of CFs with exogenous TGF-ß1 partially mimicked the epigenetic alterations observed in TAFs, suggesting that TGF-ß1 may be necessary but not sufficient to elicit such alterations. Moreover, integrated pathway-enrichment analyses of the DNA methylation alterations revealed that a fraction of TAFs may be bone marrow-derived fibrocytes. Finally, survival analyses using DNA methylation and gene expression datasets identified aberrant DNA methylation on the EDARADD promoter sequence as a prognostic factor in non-small cell lung cancer patients. Our findings shed light on the unique origin and molecular alterations underlying the aberrant phenotype of lung TAFs, and identify a stromal biomarker with potential clinical relevance.

Functional Impact and Evolution of a Novel Human Polymorphic Inversion That Disrupts a Gene and Creates a Fusion Transcript.

Despite many years of study into inversions, very little is known about their functional consequences, especially in humans. A common hypothesis is that the selective value of inversions stems in part from their effects on nearby genes, although evidence of this in natural populations is almost nonexistent. Here we present a global analysis of a new 415-kb polymorphic inversion that is among the longest ones found in humans and is the first with clear position effects. This inversion is located in chromosome 19 and has been generated by non-homologous end joining between blocks of transposable elements with low identity. PCR genotyping in 541 individuals from eight different human populations allowed the detection of tag SNPs and inversion genotyping in multiple populations worldwide, showing that the inverted allele is mainly found in East Asia with an average frequency of 4.7%. Interestingly, one of the breakpoints disrupts the transcription factor gene ZNF257, causing a significant reduction in the total expression level of this gene in lymphoblastoid cell lines. RNA-Seq analysis of the effects of this expression change in standard homozygotes and inversion heterozygotes revealed distinct expression patterns that were validated by quantitative RT-PCR. Moreover, we have found a new fusion transcript that is generated exclusively from inverted chromosomes around one of the breakpoints. Finally, by the analysis of the associated nucleotide variation, we have estimated that the inversion was generated ~40,000-50,000 years ago and, while a neutral evolution cannot be ruled out, its current frequencies are more consistent with those expected for a deleterious variant, although no significant association with phenotypic traits has been found so far.

Human inversions and their functional consequences.

Polymorphic inversions are a type of structural variants that are difficult to analyze owing to their balanced nature and the location of breakpoints within complex repeated regions. So far, only a handful of inversions have been studied in detail in humans and current knowledge about their possible functional effects is still limited. However, inversions have been related to phenotypic changes and adaptation in multiple species. In this review, we summarize the evidences of the functional impact of inversions in the human genome. First, given that inversions have been shown to inhibit recombination in heterokaryotes, chromosomes displaying different orientation are expected to evolve independently and this may lead to distinct gene-expression patterns. Second, inversions have a role as disease-causing mutations both by directly affecting gene structure or regulation in different ways, and by predisposing to other secondary arrangements in the offspring of inversion carriers. Finally, several inversions show signals of being selected during human evolution. These findings illustrate the potential of inversions to have phenotypic consequences also in humans and emphasize the importance of their inclusion in genome-wide association studies.