Crosstalk of BMP-4 and RA signaling pathways on Pomc gene regulation in corticotrophs

Retinoic acid (RA), an active metabolite of Vitamin A, and bone morphogenetic protein 4 (BMP-4) pathways control the transcription of pro-opiomelanocortin (Pomc), the precursor of ACTH. We describe a novel mechanism by which RA and BMP-4 act together in the context of pituitary corticotroph tumoral cells to regulate Pomc transcription. BMP-4 and RA exert a potentiated inhibition on Pomc gene expression. This potentiation of the inhibitory action on Pomc transcription was blocked by the inhibitory SMADs of the BMP-4 pathway (SMAD6 and SMAD7), a negative regulator of BMP-4 signaling (TOB1) and a blocker of RA pathway (COUP-TFI). AtT-20 corticotrophinoma cells express RA receptors (RARB, RXRA and RXRG) which associate with factors of BMP-4 (SMAD4 and SMAD1) signaling cascade in transcriptional complexes that block Pomc transcription. COUP-TFI and TOB1 disrupt these complexes. Deletions and mutations of the Pomc promoter and a specific DNA-binding assay show that the complexes bind to the RARE site in the Pomc promoter. The enhanced inhibitory interaction between RA and BMP-4 pathways occurs also in another relevant corticotroph gene promoter, the corticotropin-releasing hormone receptor 1 (Crh-r1). The understanding of the molecules that participate in the control of corticotroph gene expression contribute to define more precise targets for the treatment of corticotrophinomas.Fil: Nieto, Leandro Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Fuertes, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Rosmino, Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Carlos Durand; ArgentinaFil: Senin, Sergio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentin

Modifications in the cellular proteome and their clinical application

Post-translational modifications (PTMs) are covalent modifications in proteins during or after their synthesis. Among them, the best known are phosphorylation, methylation, acetylation, and also cleavage or binding of small peptides (ubiquitination, SUMOylation and NEDDylation). Often the protein is modified in multiple sites and these modifications are coordinated generating a PTMs crosstalk. Altered patterns of PTMs have been related to several pathologies. Currently, advances in mass spectrometry have made it possible to study multiple PTMs simultaneously. Oncology is one of the disciplines that incorporated these technologies for the need to better characterize tumors. In cancer, several alterations related to the ubiquitinlike PTMs have been described, such as SUMOylation. In particular, the interaction between different PTMs with SUMOylation has been studied in the context of the von Hippel Lindau (VHL) multitumoral syndrome, generating new putative biomarkers for the evolution of these tumors. RSUME or RWDD3, an enhancer of SUMOylation that acts on VHL and HIF proteins, shows a correlation with malignant parameters in this type of tumors, such as angiogenesis. Regulators of PTMs are becoming relevant as biomarkers in cancer.Fil: Elguero, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Gonilski Pacin, David Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Cárdenas Figueroa, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Fuertes, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentin

Fast pyrolysis of rice husk under vacuum conditions to produce levoglucosan

Levoglucosan (LG)-enriched pyrolytic oils were obtained from rice husk by lab-scale fast pyrolysis under vacuum conditions. We studied the effect of the pyrolysis temperature (300−700 °C) and the pretreatment of the biomass, on the pyrolysis product yields and the selectivity for LG formation. The maximum oil yield (47 wt.%) was obtained from hydrochloric acid-leached rice husk at 400 °C, producing 1.4 times more than the amount of oil produced from untreated rice husk at the same temperature. Anhydrosugars were the predominant compounds found in bio-oils under all conditions assessed, LG being the main product. Depending on the pyrolysis conditions, LG concentration was between 9−30 wt.% considering the bio-oil mass, and between 4−60 wt.% considering the initial cellulose mass. 1H NMR experiments were carried out as an alternative and simple technique to directly determine the amount of LG in bio-oils.Fil: Téllez Bernal, Jhoan Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Silva, Mariana Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales; Argentina. University of York; Reino UnidoFil: Simister, Rachael. University of York; Reino Unido. Centre For Novel Agricultural Products (cnap); Reino UnidoFil: Gomez, Leonardo Dario. University of York; Reino UnidoFil: Fuertes, Valeria Cintia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: de Paoli, Juan Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Moyano, Elizabeth Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentin

Impact of RSUME Actions on Biomolecular Modifications in Physio-Pathological Processes

The small RWD domain-containing protein called RSUME or RWDD3 was cloned from pituitary tumor cells with increasing tumorigenic and angiogenic proficiency. RSUME expression is induced under hypoxia or heat shock and is upregulated, at several pathophysiological stages, in tissues like pituitary, kidney, heart, pancreas, or adrenal gland. To date, several factors with essential roles in endocrine-related cancer appear to be modulated by RWDD3. RSUME regulates, through its post-translational (PTM) modification, pituitary tumor transforming gene (PTTG) protein stability in pituitary tumors. Interestingly, in these tumors, another PTM, the regulation of EGFR levels by USP8, plays a pathogenic role. Furthermore, RSUME suppresses ubiquitin conjugation to hypoxia-inducible factor (HIF) by blocking VHL E3-ubiquitin ligase activity, contributing to the development of von Hippel-Lindau disease. RSUME enhances protein SUMOylation of specific targets involved in inflammation such as IkB and the glucocorticoid receptor. For many of its actions, RSUME associates with regulatory proteins of ubiquitin and SUMO cascades, such as the E2-SUMO conjugase Ubc9 or the E3 ubiquitin ligase VHL. New evidence about RSUME involvement in inflammatory and hypoxic conditions, such as cardiac tissue response to ischemia and neuropathic pain, and its role in several developmental processes, is discussed as well. Given the modulation of PTMs by RSUME in neuroendocrine tumors, we focus on its interactors and its mode of action. Insights into functional implications and molecular mechanisms of RSUME action on biomolecular modifications of key factors of pituitary adenomas and renal cell carcinoma provide renewed information about new targets to treat these pathologies.Fil: Fuertes, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Elguero, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Gonilski Pacin, David Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Herbstein, Florencia Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Rosmino, Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Ciancio del Giudice, Nicolas Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Fiz, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Falcucci, Lara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentin

A novel molecular analysis approach in colorectal cancer suggests new treatment opportunities

Colorectal cancer (CRC) is a molecular and clinically heterogeneous disease. In 2015, the Colorectal Cancer Subtyping Consortium classified CRC into four consensus molecular subtypes (CMS), but these CMS have had little impact on clinical practice. The purpose of this study is to deepen the molecular characterization of CRC. A novel approach, based on probabilistic graphical models (PGM) and sparse k-means–consensus cluster layer analyses, was applied in order to functionally characterize CRC tumors. First, PGM was used to functionally characterize CRC, and then sparse k-means–consensus cluster was used to explore layers of biological information and establish classifications. To this aim, gene expression and clinical data of 805 CRC samples from three databases were analyzed. Three different layers based on biological features were identified: adhesion, immune, and molecular. The adhesion layer divided patients into high and low adhesion groups, with prognostic value. The immune layer divided patients into immune-high and immunelow groups, according to the expression of immune-related genes. The molecular layer established four molecular groups related to stem cells, metabolism, the Wnt signaling pathway, and extracellular functions. Immune-high patients, with higher expression of immune-related genes and genes involved in the viral mimicry response, may benefit from immunotherapy and viral mimicry-related therapies. Additionally, several possible therapeutic targets have been identified in each molecular group. Therefore, this improved CRC classification could be useful in searching for new therapeutic targets and specific therapeutic strategies in CRC diseas

Dating Violence : Stude with Adolescents from Heredia (Costa Rica)

RESUMEN: Gran parte del comportamiento agresivo humano se da en el contexto de una relación amorosa. El colectivo adolescente no es una excepción: las investigaciones señalan una notable prevalencia de este problema, evidenciándose la necesidad de profundizar en su estudio, especialmente en Iberoamérica, dada la escasez de trabajos al respecto. Este estudio tiene como objetivos fortalecer el conocimiento sobre el comportamiento agresivo en parejas adolescentes de Costa Rica. Para ello, se toman en consideración diferentes formas de agresión, en lugar de analizar únicamente agresiones físicas o sexuales; además se estudian posibles diferencias en función del sexo. Basándose en un diseño ex post facto, se aplica un instrumento estandarizado a 468 adolescentes de Heredia (Costa Rica), que analiza cinco formas de agresión: verbal-emocional; física; sexual; relacional y amenazas. Los resultados muestran que son escasos los participantes en la investigación que no cometieron o sufrieron alguna agresión en pareja, especialmente verbales-emocionales o verbales-emocionales y sexuales, si bien la frecuencia de estas fue baja; además, se detectan algunas diferencias significativas intersexos. De los hallazgos obtenidos se concluye la existencia de dificultades en los adolescentes para afrontar, de forma constructiva, conflictos que se presentan en sus relaciones, algo que debe ser abordado de manera integral para incrementar la eficacia de los programas preventivos para jóvenes.ABSTRACT: Most of human aggressive behavior occurs in the context of a romantic relationship. Adolescents are not an exception: research show a significant prevalence of dating violence, revealing the need for further study, especially in Latin America, given the lack of research on this topic. This study aims at strengthening knowledge about aggressive behavior in adolescent dating relationships in Costa Rica, taking into account different aggressive behaviors, not only physical or sexual abuse; differences by gender are also analyzed. Based on an ex post facto design, a standardized instrument was used to measure five types of aggressive behavior (i.e., verbal-emotional, physical, sexual, relational and threats) in a sample of 468 adolescents from Heredia (Costa Rica). Results show that most participants had committed or suffered aggressions in dating relationships, especially verbal-emotional or both verbal-emotional and sexual abuse, but the mean frequency of reported aggression was low; some significant intersex differences were also found. Results obtained indicate that adolescents have difficulties to deal with conflicts in their romantic relationship; thus this problem needs to be addressed holistically in order to increase the impact of prevention programs for youth

Tumor-Experienced Human NK Cells Express High Levels of PD-L1 and Inhibit CD8+ T Cell Proliferation

Natural Killer (NK) cells play a key role in cancer immunosurveillance. However, NK cells from cancer patients display an altered phenotype and impaired effector functions. In addition, evidence of a regulatory role for NK cells is emerging in diverse models of viral infection, transplantation, and autoimmunity. Here, we analyzed clear cell renal cell carcinoma (ccRCC) datasets from The Cancer Genome Atlas (TCGA) and observed that a higher expression of NK cell signature genes is associated with reduced survival. Analysis of fresh tumor samples from ccRCC patients unraveled the presence of a high frequency of tumor-infiltrating PD-L1+ NK cells, suggesting that these NK cells might exhibit immunoregulatory functions. In vitro, PD-L1 expression was induced on NK cells from healthy donors (HD) upon direct tumor cell recognition through NKG2D and was further up-regulated by monocyte-derived IL-18. Moreover, in vitro generated PD-L1hi NK cells displayed an activated phenotype and enhanced effector functions compared to PD-L1- NK cells, but simultaneously, they directly inhibited CD8+ T cell proliferation in a PD-L1-dependent manner. Our results suggest that tumors might drive the development of PD-L1-expressing NK cells that acquire immunoregulatory functions in humans. Hence, rational manipulation of these regulatory cells emerges as a possibility that may lead to improved anti-tumor immunity in cancer patients.Fil: Sierra, Jessica Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Secchiari, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Nuñez, Sol Yanel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Raffo Iraolagoitia, Ximena Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ziblat, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Friedrich, Adrián David. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Cátedra de Inmunología; ArgentinaFil: Regge, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Santilli, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Torres, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gantov, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Trotta, Aldana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ameri, Carlos Enrique. Hospital Alemán; ArgentinaFil: Vitagliano, Gonzalo. Hospital Alemán; ArgentinaFil: Ríos Pita, Hernando. Hospital Alemán; ArgentinaFil: Rico, Luis. Hospital Alemán; ArgentinaFil: Rovegno, Agustín. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Richards, Nicolás. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Domaica, Carolina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Zwirner, Norberto Walter. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fuertes, Mercedes Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Expansion of CD11b⁺Ly6G⁺Ly6C^int cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions

The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b⁺Gr-1⁺, mostly CD11b⁺Ly6G⁺Ly6Cint and CD11b⁺Ly6G⁻Ly6Chigh cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance. We used the highly metastatic 4T1 breast tumor (which does not express the classical progesterone receptor and expands MDSCs) to challenge BALB/c mice in the absence or in the presence of MPA. We observed that MPA promoted the accumulation of NK cells in spleens of tumor-bearing mice, but with reduced degranulation ability and in vivo cytotoxic activity. Simultaneously, MPA induced a preferential expansion of CD11b⁺Ly6G⁺Ly6Cint cells in spleen and bone marrow of 4T1 tumor-bearing mice. In vitro, MPA promoted nuclear mobilization of the glucocorticoid receptor (GR) in 4T1 cells and endowed these cells with the ability to promote a preferential differentiation of bone marrow cells into CD11b⁺Ly6G⁺Ly6Cint cells that displayed suppressive activity on NK cell degranulation. Sorted CD11b⁺Gr-1⁺ cells from MPA-treated tumor-bearing mice exhibited higher suppressive activity on NK cell degranulation than CD11b⁺Gr-1⁺ cells from vehicle-treated tumor-bearing mice. Thus, MPA, acting through the GR, endows tumor cells with an enhanced capacity to expand CD11b⁺Ly6G⁺Ly6Cint cells that subsequently display a stronger suppression of NK cell-mediated anti-tumor immunity. Our results describe an alternative mechanism by which MPA may affect immunosurveillance and have potential implication in breast cancer incidence.Facultad de Ciencias Exacta

Genetic correction of PSA values using sequence variants associated with PSA levels

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldMeasuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.info:eu-repo/grantAgreement/EC/FP7/202059/ 218071 Urological Research Foundation P50 CA90386-05S2 Robert H. Lurie Comprehensive Cancer Center p30 CA60553 Health Technology Assessment Programme 96/20/06 96/20/99 Department of Health, England Cancer Research UK C522/A8649 Medical Research Council of England G0500966 ID 75466 National Cancer Research Institute (NCRI), UK Southwest National Health Service Research and Development NCRI National Institute for Health Resear

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues