Genetically predicted circulating protein biomarkers and ovarian cancer risk.

OBJECTIVE: Most women with epithelial ovarian cancer (EOC) are diagnosed after the disease has metastasized and survival in this group remains poor. Circulating proteins associated with the risk of developing EOC have the potential to serve as biomarkers for early detection and diagnosis. We integrated large-scale genomic and proteomic data to identify novel plasma proteins associated with EOC risk. METHODS: We used the germline genetic variants most strongly associated (P <1.5 × 10-11) with plasma levels of 1329 proteins in 3301 healthy individuals from the INTERVAL study to predict circulating levels of these proteins in 22,406 EOC cases and 40,941 controls from the Ovarian Cancer Association Consortium (OCAC). Association testing was performed by weighting the beta coefficients and standard errors for EOC risk from the OCAC study by the inverse of the beta coefficients from INTERVAL. RESULTS: We identified 26 proteins whose genetically predicted circulating levels were associated with EOC risk at false discovery rate < 0.05. The 26 proteins included MFAP2, SEMG2, DLK1, and NTNG1 and a group of 22 proteins whose plasma levels were predicted by variants at chromosome 9q34.2. All 26 protein association signals identified were driven by association with the high-grade serous histotype that comprised 58% of the EOC cases in OCAC. Regional genomic plots confirmed overlap of the genetic association signal underlying both plasma protein level and EOC risk for the 26 proteins. Pathway analysis identified enrichment of seven biological pathways among the 26 proteins (Padjusted <0.05), highlighting roles for Focal Adhesion-PI3K-Akt-mTOR and Notch signaling. CONCLUSION: The identified proteins further illuminate the etiology of EOC and represent promising new EOC biomarkers for targeted validation by studies involving direct measurement of plasma proteins in EOC patient cohorts

Risk Factors for Acute Leukemia in Children: A Review

Although overall incidence is rare, leukemia is the most common type of childhood cancer. It accounts for 30% of all cancers diagnosed in children younger than 15 years. Within this population, acute lymphocytic leukemia (ALL) occurs approximately five times more frequently than acute myelogenous leukemia (AML) and accounts for approximately 78% of all childhood leukemia diagnoses. Epidemiologic studies of acute leukemias in children have examined possible risk factors, including genetic, infectious, and environmental, in an attempt to determine etiology. Only one environmental risk factor (ionizing radiation) has been significantly linked to ALL or AML. Most environmental risk factors have been found to be weakly and inconsistently associated with either form of acute childhood leukemia. Our review focuses on the demographics of childhood leukemia and the risk factors that have been associated with the development of childhood ALL or AML. The environmental risk factors discussed include ionizing radiation, non-ionizing radiation, hydrocarbons, pesticides, alcohol use, cigarette smoking, and illicit drug use. Knowledge of these particular risk factors can be used to support measures to reduce potentially harmful exposures and decrease the risk of disease. We also review genetic and infectious risk factors and other variables, including maternal reproductive history and birth characteristics

Mental health of female foreign spouses in transnational marriages in southern Taiwan

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate the mental health status, and the risk factors associated with mild psychiatric disorders, of female foreign spouses (from Vietnam, Indonesia, and mainland China) in southern Taiwan, and to understand the mental health needs of these women.</p> <p>Methods</p> <p>One hundred and twenty nine participants were willing to participate in this study. All participants fulfilled all questionnaires which included demographic information, the Chinese Health Questionnaire (CHQ), the Eysenck Personality Questionnaire (EPQ), and the Mental Health Care Needs Questionnaire (MHCNQ).</p> <p>Results</p> <p>By multiple linear regression, neuroticism characteristics (p = 0.000), the dimension of knowledge of the level of their own psychological disturbance (p = 0.001), dimension of friends assistance (p = 0.033), and dimension of religion comfort (p = 0.041) in mental health care needs could be used to predict possible mild psychiatric disorders. Furthermore, SEM model showed that Indonesian or Vietnamese spouses have more likely degree in mental health care needs (β = -0.24, <it>p </it>= 0.003), compared with Chinese ones. A higher level of neuroticism was associated with a greater likelihood of mild psychiatric disorder (β = 0.54, <it>p </it>< 0.001), and of mental health care needs (β = 0.21, <it>p </it>= 0.013). A higher degree of mental health care needs was related to a greater likelihood of mild psychiatric disorder (β = 0.14, <it>p </it>= 0.05).</p> <p>Conclusion</p> <p>In conclusion, we have obtained a better understanding of the mental health status of female foreign spouses in transnational marriages, who face many difficulties. Indonesian or Vietnamese spouses tend to more likely degree in mental health care needs than Chinese spouses, and then indirectly influenced their mental health status. Some individuals with a neurotic personality are exposed to high risk and might suffer from mild psychiatric symptoms. The needs for psychological counseling and religion therapy were the first priority for these women, particularly the Indonesian and Vietnamese spouses. From these findings, we have a better understanding of how to assist these female foreign spouses in future.</p

Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk.

A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large-scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse-variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin-like growth factor receptor 1 and other membrane receptors (OR: 0.82-1.18, p values: 6.96 × 10-4 -3.28 × 10-8 ), are linked to insulin resistance and estrogen receptor signaling pathways. Proteins identified at other loci include those involved in biological processes such as alcohol and lipid metabolism, proteolysis, apoptosis, immune regulation and cell motility and proliferation. Consistent associations were observed for 22 proteins in the UK Biobank data (p < 0.05). The study identifies potential novel biomarkers for breast cancer, but further investigation is needed to replicate our findings.Includes CRUK and FP7

Clusters of Basic Amino Acids Contribute to RNA Binding and Nucleolar Localization of Ribosomal Protein L22

The ribosomal protein L22 is a component of the 60S eukaryotic ribosomal subunit. As an RNA-binding protein, it has been shown to interact with both cellular and viral RNAs including 28S rRNA and the Epstein-Barr virus encoded RNA, EBER-1. L22 is localized to the cell nucleus where it accumulates in nucleoli. Although previous studies demonstrated that a specific amino acid sequence is required for nucleolar localization, the RNA-binding domain has not been identified. Here, we investigated the hypothesis that the nucleolar accumulation of L22 is linked to its ability to bind RNA. To address this hypothesis, mutated L22 proteins were generated to assess the contribution of specific amino acids to RNA binding and protein localization. Using RNA-protein binding assays, we demonstrate that basic amino acids 80–93 are required for high affinity binding of 28S rRNA and EBER-1 by L22. Fluorescence localization studies using GFP-tagged mutated L22 proteins further reveal that basic amino acids 80–93 are critical for nucleolar accumulation and for incorporation into ribosomes. Our data support the growing consensus that the nucleolar accumulation of ribosomal proteins may not be mediated by a defined localization signal, but rather by specific interaction with established nucleolar components such as rRNA

High viral load of Merkel cell polyomavirus DNA sequences in Langerhans cell sarcoma tissues.

International audienceBACKGROUND: Langerhans cell (LC) sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytologic features and an LC phenotype. We very recently suggested that LC behaves as a reservoir for common dermotropic Merkel cell polyomavirus (MCPyV) and determined the relationship between LC histiocytosis (LCH), which has an underlining oncogenic capacity, and MCPyV as a trigger for a reactive process rather than a neoplastic process. We propose LC to be a reservoir for MCPyV and hypothesize that some LCS subtypes may be related to the MCPyV agent. FINDINGS: We examined seven LCS tissues using multiplex quantitative PCR (Q-PCR) and immunohistochemistry with anti MCPyV large-T (LT) antigen antibody. High viral loads of MCPyV DNA sequences (viral load = relative levels of MCPyV) were detected (0.328-0.772 copies/cell (Merkel cell carcinoma (MCC) = 1.0)) using Q-PCR in 43% (3/7) tissues, but LT antigen expression was not observed (0/7). CONCLUSIONS: Frequent MCPyV-DNA amplification suggests that LCS in some patients may be related to MCPyV infection. Moreover, the higher viral load of LCS (median, 0.453 copies/cell) than low load of LCH (0.003, median of 12 cases) (P < 0.01) may suggest a virally induced tumorigenic process in some LCS. Although the absence of LT antigen expression may indicate a different role for MCPyV in this pathology, some subtypes of LCS may develop in the background of MCPyV-infected LC. To the best of our knowledge, this is the first report on the relationship between MCPyV and LCS. The recent discovery of MCPyV opened new therapeutic avenues for MCC. These data open novel possibilities for therapeutic interventions against LCS

Substrate Reduction Augments the Efficacy of Enzyme Therapy in a Mouse Model of Fabry Disease

Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease

The Dynamical Structure and Evolution of Giant Molecular Clouds

Giant molecular clouds (GMCs) are the sites of star formation in the Galaxy. Many of their properties can be understood in terms of a model in which the GMCs and the star-forming clumps within them are in approximate pressure equilibrium, with turbulent motions treated as a separate pressure component