C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis

Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits.</p

Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits.

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene-trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits

DDAO Controlled Synthesis of Organo-Modified Silica Nanoparticles with Encapsulated Fluorescent Boron Dipyrrins and Study of Their Uptake by Cancerous Cells

The design of cargo carriers with high biocompatibility, unique morphological characteristics, and capability of strong bonding of fluorescent dye is highly important for the development of a platform for smart imaging and diagnostics. In this paper, BODIPY-doped silica nanoparticles were prepared through a "one-pot" soft-template method using a sol-gel process. Several sol-gel precursors have been used in sol-gel synthesis in the presence of soft-template to obtain the silica-based materials with the most appropriate morphological features for the immobilization of BODIPY molecules. Obtained silica particles have been shown to be non-cytotoxic and can be effectively internalized into the cervical cancer cell line (HeLa). The described method of synthesis allows us to obtain silica-based carriers with an immobilized fluorescent dye that provide the possibility for real-time imaging and detection of these carriers

Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome.

Comparing transcript levels between healthy and diseased individuals allows the identification of differentially expressed genes, which may be causes, consequences or mere correlates of the disease under scrutiny. We propose a method to decompose the observational correlation between gene expression and phenotypes driven by confounders, forward- and reverse causal effects. The bi-directional causal effects between gene expression and complex traits are obtained by Mendelian Randomization integrating summary-level data from GWAS and whole-blood eQTLs. Applying this approach to complex traits reveals that forward effects have negligible contribution. For example, BMI- and triglycerides-gene expression correlation coefficients robustly correlate with trait-to-expression causal effects (r &lt;sub&gt;BMI &lt;/sub&gt; = 0.11, P &lt;sub&gt;BMI &lt;/sub&gt; = 2.0 × 10 &lt;sup&gt;-51&lt;/sup&gt; and r &lt;sub&gt;TG &lt;/sub&gt; = 0.13, P &lt;sub&gt;TG &lt;/sub&gt; = 1.1 × 10 &lt;sup&gt;-68&lt;/sup&gt; ), but not detectably with expression-to-trait effects. Our results demonstrate that studies comparing the transcriptome of diseased and healthy subjects are more prone to reveal disease-induced gene expression changes rather than disease causing ones

GENE-CELL THERAPY OF HIV AND HEMATOLOGICAL MALIGNANCES BASED ON HEMATOPOIETIC STEM CELL TRANSPLANTATION AND SITE-SPECIFIC GENOME EDITING

Based on the annual UNAIDS reports the number of HIVinfected patients is continually growing since 1983. Antiretroviral Therapy (ART) allows to prolong life expectancy, but the problem of life quality and overall survival is still remaining. Nowadays, in the era of ART, one of the main cause of mortality in HIV-infected patients is malignancies. Lymphomas play one of the key roles in this group of diseases. The treatment of lymphomas includes combined regiments of chemotherapy with a curative potential. High dose chemotherapy with autologous hematopoietic stem cell transplant (auto-HSCT) is the main path of the treatment for relapsed / refractory lymphomas. In the last few years with a development of the genome editing technology auto-HSCT is becoming one of the most promising methods of HIV treatment. The case of “Berlin patient” when allogeneic HSCT from donor with mutation CCR5-delta32 lead to cure from HIV and proof of concept the efficacy of the gene therapy for HIV based on HSCT. Hematopoietic stem cell transplantation with edited autologous HSC (CCR5 knockout by site-specific genome editing tools with engineering nucleases) is a comprehensive treatment for this cohort of patients. On one hand, high dose chemotherapy with auto-HSCT cures the malignancy; on the other hand auto-HSCT works as a delivery method for the edited cells and creates an environment for the HIV eradication. This review is dedicated to HIV and oncology, methods of treatment of hematological malignancies and HIV-infection using genome editing technology based on HSCT

Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia : Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age

PURPOSE Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse. (C) 2019 by American Society of Clinical OncologyPeer reviewe

An exploratory phenome wide association study linking asthma and liver disease genetic variants to electronic health records from the Estonian Biobank

<div><p>The Estonian Biobank, governed by the Institute of Genomics at the University of Tartu (Biobank), has stored genetic material/DNA and continuously collected data since 2002 on a total of 52,274 individuals representing ~5% of the Estonian adult population and is increasing. To explore the utility of data available in the Biobank, we conducted a phenome-wide association study (PheWAS) in two areas of interest to healthcare researchers; asthma and liver disease. We used 11 asthma and 13 liver disease-associated single nucleotide polymorphisms (SNPs), identified from published genome-wide association studies, to test our ability to detect established associations. We confirmed 2 asthma and 5 liver disease associated variants at nominal significance and directionally consistent with published results. We found 2 associations that were opposite to what was published before (rs4374383:AA increases risk of NASH/NAFLD, rs11597086 increases ALT level). Three SNP-diagnosis pairs passed the phenome-wide significance threshold: rs9273349 and E06 (thyroiditis, p = 5.50x10^-8); rs9273349 and E10 (type-1 diabetes, p = 2.60x10^-7); and rs2281135 and K76 (non-alcoholic liver diseases, including NAFLD, p = 4.10x10^-7). We have validated our approach and confirmed the quality of the data for these conditions. Importantly, we demonstrate that the extensive amount of genetic and medical information from the Estonian Biobank can be successfully utilized for scientific research.</p></div

ГЕННАЯ КЛЕТОЧНАЯ ТЕРАПИЯ ВИЧ И ЗЛОКАЧЕСТВЕННЫХ ОПУХОЛЕЙ КРОВЕТВОРНОЙ И ЛИМФАТИЧЕСКОЙ ТКАНИ НА ОСНОВЕ ТРАНСПЛАНТАЦИИ ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК С ИСПОЛЬЗОВАНИЕМ САЙТ-СПЕЦИФИЧЕСКОГО РЕДАКТИРОВАНИЯ ГЕНОМА

Based on the annual UNAIDS reports the number of HIVinfected patients is continually growing since 1983. Antiretroviral Therapy (ART) allows to prolong life expectancy, but the problem of life quality and overall survival is still remaining. Nowadays, in the era of ART, one of the main cause of mortality in HIV-infected patients is malignancies. Lymphomas play one of the key roles in this group of diseases. The treatment of lymphomas includes combined regiments of chemotherapy with a curative potential. High dose chemotherapy with autologous hematopoietic stem cell transplant (auto-HSCT) is the main path of the treatment for relapsed / refractory lymphomas. In the last few years with a development of the genome editing technology auto-HSCT is becoming one of the most promising methods of HIV treatment. The case of “Berlin patient” when allogeneic HSCT from donor with mutation CCR5-delta32 lead to cure from HIV and proof of concept the efficacy of the gene therapy for HIV based on HSCT. Hematopoietic stem cell transplantation with edited autologous HSC (CCR5 knockout by site-specific genome editing tools with engineering nucleases) is a comprehensive treatment for this cohort of patients. On one hand, high dose chemotherapy with auto-HSCT cures the malignancy; on the other hand auto-HSCT works as a delivery method for the edited cells and creates an environment for the HIV eradication. This review is dedicated to HIV and oncology, methods of treatment of hematological malignancies and HIV-infection using genome editing technology based on HSCT.По данным ежегодных докладов UNAIDS, c1983 г. количество ВИЧ-инфицированных пациентов неуклонно растет. Антиретровирусная терапия (АРВТ) позволяет увеличить продолжительность жизни, но проблемы качества жизни и долгосрочной выживаемости не решены. Одной из основных причин летальности у пациентов с ВИЧ в эру АРВТ являются онкологические заболевания, среди которых значительную часть составляют злокачественные лимфомы. Лечение лимфом включает этапную противоопухолевую химиотерапию (ПХТ) с потенциалом полного излечения пациента. Высокодозная ПХТ с аутологичной трансплантацией гемопоэтических стволовых клеток (ТГСК) – основное средство лечения рецидивов и рефрактерных форм агрессивных злокачественных лимфом. В последние годы с появлением технологии редактирования генома аутологичная ТГСК становится также одним из самых перспективных методов лечения ВИЧ-инфекции. История излечения от ВИЧ «Берлинского пациента» благодаря аллогенной ТГСК от донора с мутацией гена CCR5 продемонстрировала эффективность подхода генной терапии на основе трансплантации. Высокодозная химиотерапия с трансплантацией аутологичных, подвергнутых редактированию (инактивации гена CCR5, с помощью генно-инженерных нуклеаз), гемопоэтических стволовых клеток потенциально представляет собой способ комплексного лечения этих пациентов. С одной стороны, высокодозная ПХТ с ауто-ТГСК обеспечивает излечение от злокачественной опухоли, с другой стороны, она является способом доставки отредактированных клеток и создания условий для реализации лечебного эффекта против ВИЧ.Данный обзор посвящён методам лечения опухолей кроветворной и лимфатической ткани и ВИЧинфекции с использованием редактирования генома на основе трансплантации гемопоэтических стволовых клеток.