👤 Ramon Alemany

Abnormal circulating lipid levels have been suggested in relation to lymphoid malignancy (LM) risk. We studied UK Biobank participants (n = 403,625) with serum data for cholesterol (total [TC], high-density lipoprotein [HDL], direct low-density lipoprotein [LDL]), triglycerides (TG), and apolipoproteins A1 and B (ApoA1, ApoB). We conducted principal component (PC) analysis and multivariate Cox regression models to estimate hazard ratio (HR) overall, by lipid-lowering drug use and follow-up interval. During an average of 10.5 years of follow-up, 3006 incident LMs occurred (including 667 multiple myelomas [MM], 2193 non-Hodgkin lymphomas [NHL]). Among medication non-users, most lipid levels were inversely associated with risk of most endpoints (HR Lipid depletion closer to LM diagnosis might reflect cancer cell metabolism and warrants further work examining individuals with precursor conditions. The MM-specific long-term risk might reflect the known MM-obesity association. Show less

G-quadruplexes (G4s) are prevalent DNA structures that regulate transcription but also threaten genome stability. How G4 dynamics are controlled remains poorly understood. Here, we report that RNA transcripts govern G4 landscapes through coordinated G-loop assembly and disassembly. G-loop assembly involves activation of the ATM and ATR kinases, followed by homology-directed invasion of RNA opposite the G4 strand mediated by BRCA2 and RAD51. Disassembly of the G-loop resolves the G4 structure through DHX36-FANCJ-mediated G4 unwinding, which triggers nucleolytic incision and subsequent hybrid strand renewal by DNA synthesis. Inhibition of G-loop disassembly causes global G4 and R-loop accumulation, leading to transcriptome dysregulation, replication stress, and genome instability. These findings establish an intricate G-loop assembly-disassembly mechanism that controls G4 landscapes and is essential for cellular homeostasis and survival. Show less

Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, but most tumors show resistance. Resistance is connected to a non-T cell inflamed phenotype partially caused by a lack of functional dendritic cells (DCs) that are crucial for T cell priming. Herein, we investigated whether the adenoviral gene vehicle mLOAd703 carrying both DC- and T cell-activating genes can lead to inflammation in a B16-CD46 model and thereby overcome resistance to checkpoint inhibition therapy. B16-CD46 cells were injected subcutaneously in one or both flanks of immunocompetent C57BL/6J mice. mLOAd703 treatments were given intratumorally alone or in combination with intraperitoneal checkpoint inhibition therapy (anti-PD-1, anti-PD-L1, or anti-TIM-3). Tumor, lymph node, spleen, and serum samples were analyzed for the presence of immune cells and cytokines/chemokines. B16-CD46 tumors were non-inflamed and resistant to checkpoint blockade. In contrast, mLOAd703 treatment led to infiltration of the tumor by CD8 Show less

Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) are promising gene therapy vectors. Both display liver tropism and are currently thought to enter hepatocytes in vivo through cell surface heparan sulfate proteoglycans (HSPGs). To test directly this hypothesis, we created mice that lack Ext1, an enzyme required for heparan sulfate biosynthesis, in hepatocytes. Ext1(HEP) mutant mice exhibit an 8-fold reduction of heparan sulfate in primary hepatocytes and a 5-fold reduction of heparan sulfate in whole liver tissue. Conditional hepatocyte Ext1 gene deletion greatly reduced AAV2 liver transduction following intravenous injection. Ad5 transduction requires blood coagulation factor X (FX); FX binds to the Ad5 capsid hexon protein and bridges the virus to HSPGs on the cell surface. Ad5.FX transduction was abrogated in primary hepatocytes from Ext1(HEP) mice. However, in contrast to the case with AAV2, Ad5 transduction was not significantly reduced in the livers of Ext1(HEP) mice. FX remained essential for Ad5 transduction in vivo in Ext1(HEP) mice. We conclude that while AAV2 requires HSPGs for entry into mouse hepatocytes, HSPGs are dispensable for Ad5 hepatocyte transduction in vivo. This study reopens the question of how adenovirus enters cells in vivo. Our understanding of how viruses enter cells, and how they can be used as therapeutic vectors to manage disease, begins with identification of the cell surface receptors to which viruses bind and which mediate viral entry. Both adeno-associated virus 2 and adenovirus 5 are currently thought to enter hepatocytes in vivo through heparan sulfate proteoglycans (HSPGs). However, direct evidence for these conclusions is lacking. Experiments presented herein, in which hepatic heparan sulfate synthesis was genetically abolished, demonstrated that HSPGs are not likely to function as hepatocyte Ad5 receptors in vivo. The data also demonstrate that HSPGs are required for hepatocyte transduction by AAV2. These results reopen the question of the identity of the Ad5 receptor in vivo and emphasize the necessity of demonstrating the nature of the receptor by genetic means, both for understanding Ad5 entry into cells in vivo and for optimization of Ad5 vectors as therapeutic agents. Show less

Attention deficit is one of the core symptoms of the attention-deficit/hyperactivity disorder (ADHD). However, the specific genetic variants that may be associated with attention function in adult ADHD remain largely unknown. The present study aimed to identifying SNPs associated with attention function in adult ADHD and tested whether these associations were enriched for specific biological pathways. Commissions, hit-reaction time (HRT), the standard error of HRT (HRTSE), and intraindividual coefficient variability (ICV) of the Conners Continuous Performance Test (CPT-II) were assessed in 479 unmedicated adult ADHD individuals. A Genome-Wide Association Study (GWAS) was conducted for each outcome and, subsequently, gene set enrichment analyses were performed. Although no SNPs reached genome-wide significance (P < 5E-08), 27 loci showed suggestive evidence of association with the CPT outcomes (P < E-05). The most relevant associated SNP was located in the SORCS2 gene (P = 3.65E-07), previously associated with bipolar disorder (BP), Alzheimer disease (AD), and brain structure in elderly individuals. We detected other genes suggested to be involved in synaptic plasticity, cognitive function, neurological and neuropsychiatric disorders, and smoking behavior such as NUAK1, FGF20, NETO1, BTBD9, DLG2, TOP3B, and CHRNB4. Also, several of the pathways nominally associated with the CPT outcomes are relevant for ADHD such as the ubiquitin proteasome, neurodegenerative disorders, axon guidance, and AD amyloid secretase pathways. To our knowledge, this is the first GWAS and pathway analysis of attention function in patients with persistent ADHD. Overall, our findings reinforce the conceptualization of attention function as a potential endophenotype for studying the molecular basis of adult ADHD. © 2015 Wiley Periodicals, Inc. Show less