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Methamphetamine use disorder has emerged as a significant public health concern globally. This study endeavors to elucidate the alterations in expression changes of miRNAs in the plasma of methamphetamine use disorder and elucidate the alterations in miRNA expression in the plasma of individuals with methamphetamine use disorder and investigate the relationship between these differentially expressed miRNAs and the disorder itself, cravings for methamphetamine, and associated mental disorders. Furthermore, the study seeks to clarify the expression of downstream target molecules of specific miRNAs in the plasma of methamphetamine use disorder, assess the diagnostic utility of these miRNAs and their target molecules, explore their potential as biomarkers, and identify potential targets for the diagnosis and treatment of methamphetamine use disorder. The research subjects included 112 individuals with methamphetamine use disorder and 112 healthy controls. A questionnaire was utilized to gather baseline information on methamphetamine use disorder, assess craving for methamphetamine using a Visual Analog Scale (VAS), and evaluate anxiety (SAS) and depression (SDS) states. Employing qRT-PCR technology, we measured the expression levels of miR-9-3p and let-7b-3p in the plasma of those with the disorder. Bioinformatics tools were then used to predict downstream target molecules. Western blot analysis was conducted to quantify the levels of these target molecules in the plasma. Receiver operating characteristic (ROC) curves were utilized to evaluate the diagnostic accuracy of miRNAs and their target molecules. Additionally, we analyzed the correlation between the miRNA expression levels and the psychiatric symptoms of methamphetamine use disorder. The qRT-PCR results revealed that the expression levels of miR-9-3p and let-7b-3p were significantly elevated in the plasma of individuals with methamphetamine use disorder compared to healthy controls (P < 0.05). Furthermore, qRT-PCR and Western blot analyses demonstrated that transfection with miR-9-3p mimic led to overexpression of miR-9-3p, while transfection with let-7-3p mimic promoted overexpression of let-7-3p, concurrently inhibiting the protein levels of BDNF and GSK3B in cells (P < 0.05); ROC curve analysis indicated that the AUC for miR-9-3p was 0.782 (95% CI 0.716-0.848) and for let-7b-3p was 0.720 (95% CI 0.650-0.789). However, Spearman correlation analysis showed no significant association between the expression levels of target miRNAs and proteins and the psychiatric symptoms of methamphetamine use disorder. Notably, the combination of miR-9-3p, let-7b-3p, and BDNF exhibited high diagnostic accuracy for methamphetamine use disorder, suggesting their potential as biomarkers for its diagnosis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines. The original Cancer Cell Line Encyclopedia (CCLE) is expanded with deeper characterization of over 1,000 cell lines, including genomic, transcriptomic, and proteomic data, and integration with drug-sensitivity and gene-dependency data., Author(s): Mahmoud Ghandi [sup.1] , Franklin W. Huang [sup.1] [sup.2] [sup.13] , Judit Jané-Valbuena [sup.1] [sup.2] , Gregory V. Kryukov [sup.1] , Christopher C. Lo [sup.1] , E. Robert McDonald [...]

Background/objectives The objective of this study was to evaluate the performance of a short food frequency questionnaire (FFQ) to assess dietary intake at 4 and 7 years of age, against 3d food diaries (FD) and serum biomarkers, using two methods to convert the FFQ to daily intake in grams and nutrients (standard and z-score method). Subjects/methods The present analysis comprises data from 2482 4-year-old children and 3511 7-year-old children, from the birth cohort Generation XXI (Porto, Portugal). To estimate daily consumption from the FFQ, the frequency response was multiplied by a standard mean portion (standard method) or adjusted with data from the FD (z-score method). The dietary intake obtained from the FFQ was compared with the FD and serum biomarkers, using Intra-Class Correlation Coefficients (ICC), de-attenuated Pearson's correlation coefficients and Bland Altman analysis. Results In general, the mean daily food intake estimated by the z-score method had a higher agreement with the FD, than the standard method. The highest ICC was obtained for 'vegetable soup' (ICC = 0.536), using the z-score method, compared to an ICC of 0.373 using the standard method. Significant correlation coefficients were observed for all nutrients; the average of correlation coefficients was 0.39 at 4 years and 0.42 at 7 years of age. For the majority of nutrients, the correlation between mean and mean difference was lower using the z-score method, in comparison with the standard method. Conclusions The results suggest that the FFQ is a reasonably good instrument to estimate dietary intake in children. Moreover, adjusting the FFQ portion size, by using a z-score method, seems to increase the accuracy of dietary data in children., Author(s): Sofia Vilela [sup.1] [sup.2], Milton Severo [sup.1] [sup.2], Teresa Moreira [sup.1] [sup.2], Elisabete Ramos [sup.1] [sup.2], Carla Lopes [sup.1] [sup.2] Author Affiliations: (1) EPIUnit - Instituto de Saúde Pública, [...]

Background: Causes of most childhood hematopoietic neoplasms are unknown. Early age of occurrence suggests prenatal etiology. Positive associations have been reported between industrially produced trans-fatty acids (iTFAs) and risks of some cancers in adults. iTFAs are pro-inflammatory and adversely affect the beneficial effects of essential fatty acids, the latter is diminishing tumor growth. In 2004 Denmark legislated against the use of iTFA in foodstuffs. Using the entire population, we investigated if the changes in the legislation as a proxy to the reduced exposure to iTFA had affected the incidence of childhood hematopoietic neoplasms. Methods: We used a Cox proportional hazard model to compare the hazard of childhood hematopoietic neoplasms among children born before and after the iTFA ban, as a proxy for fetal iTFA exposure. To take the potential secular trend in hematopoietic neoplasms into account, we modeled the variation in cancer risk across birth cohorts by a piecewise linear spline with a knot in 2004, which allowed a comparison of the hazard of childhood hematopoietic neoplasms between the time before and after the iTFA ban. Results: Among children born in 1988-2008 in Denmark, 720 were diagnosed with hematopoietic neoplasms before the age of 7 years, corresponding to an overall incidence rate of 7.6 per 100 000 person years. The incidence rates increased by 2% per cohort in 1988-2004 (hazard ratio: 1.02 [1.01; 1.04]) and in 2004-2008 (hazard ratio: 1.02 [0.95; 1.11]). Conclusions: No apparent benefit of the iTFA legislation in reducing childhood hematopoietic neoplasms was observed on population basis. Individual-level data are needed to investigate any possible associations between biomarkers of iTFA intake and risk of childhood hematopoietic neoplasms., Author(s): Ina Olmer Specht [sup.1] , Inge Huybrechts [sup.2] , Peder Frederiksen [sup.1] , Eva Steliarova-Foucher [sup.3] , Veronique Chajes [sup.2] , Berit Lilienthal Heitmann [sup.1] [sup.4] [sup.5] Author Affiliations: [...]

Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit.sup.1,2. Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection.sup.3-11. Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients.sup.12,13. Such a technique, however, requires substantial clinical development and validation. Here we present the initial results from a first-in-human study to assess the feasibility of imaging with zirconium-89-labeled atezolizumab (anti-PD-L1), including biodistribution, and secondly test its potential to predict response to PD-L1 blockade (ClinicalTrials.gov identifiers NCT02453984 and NCT02478099). We imaged 22 patients across three tumor types before the start of atezolizumab therapy. The PET signal, a function of tracer exposure and target expression, was high in lymphoid tissues and at sites of inflammation. In tumors, uptake was generally high but heterogeneous, varying within and among lesions, patients, and tumor types. Intriguingly, clinical responses in our patients were better correlated with pretreatment PET signal than with immunohistochemistry- or RNA-sequencing-based predictive biomarkers, encouraging further development of molecular PET imaging for assessment of PD-L1 status and clinical response prediction. Initial results from a first-in-human study show that PET imaging with PD-L1 antibodies outperforms immunohistochemistry- or RNA-sequencing-based biomarkers for prediction of clinical response to immunotherapy., Author(s): Frederike Bensch [sup.1] , Elly L. van der Veen [sup.1] , Marjolijn N. Lub-de Hooge [sup.2] [sup.3] , Annelies Jorritsma-Smit [sup.2] , Ronald Boellaard [sup.3] , Iris C. Kok [...]

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.Deep phenotype and genome-wide genetic data from 500,000 individuals from the UK Biobank, describing population structure and relatedness in the cohort, and imputation to increase the number of testable variants to 96 million., Author(s): Clare Bycroft [sup.1] , Colin Freeman [sup.1] , Desislava Petkova [sup.1] [sup.12] , Gavin Band [sup.1] , Lloyd T. Elliott [sup.2] , Kevin Sharp [sup.2] , Allan Motyer [sup.3] [...]

Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research. An algorithm-selected gene signature focused on tumor immune evasion and suppression predicts response to immune checkpoint blockade in melanoma, exceeding the accuracy of current clinical biomarkers., Author(s): Peng Jiang [sup.1] [sup.2] , Shengqing Gu [sup.3] , Deng Pan [sup.4] [sup.5] , Jingxin Fu [sup.6] , Avinash Sahu [sup.1] [sup.2] , Xihao Hu [sup.1] [sup.2] , Ziyi [...]

Prolonged exposure to microbial products such as lipopolysaccharide can induce a form of innate immune memory that blunts subsequent responses to unrelated pathogens, known as lipopolysaccharide tolerance. Sepsis is a dysregulated systemic immune response to disseminated infection that has a high mortality rate. In some patients, sepsis results in a period of immunosuppression (known as 'immunoparalysis').sup.1 characterized by reduced inflammatory cytokine output.sup.2, increased secondary infection.sup.3 and an increased risk of organ failure and mortality.sup.4. Lipopolysaccharide tolerance recapitulates several key features of sepsis-associated immunosuppression.sup.5. Although various epigenetic changes have previously been observed in tolerized macrophages.sup.6-8, the molecular basis of tolerance, immunoparalysis and other forms of innate immune memory has remained unclear. Here we perform a screen for tolerance-associated microRNAs and identify miR-221 and miR-222 as regulators of the functional reprogramming of macrophages during lipopolysaccharide tolerization. Prolonged stimulation with lipopolysaccharide in mice leads to increased expression of miR-221 and mir-222, both of which regulate brahma-related gene 1 (Brg1, also known as Smarca4). This increased expression causes the transcriptional silencing of a subset of inflammatory genes that depend on chromatin remodelling mediated by SWI/SNF (switch/sucrose non-fermentable) and STAT (signal transducer and activator of transcription), which in turn promotes tolerance. In patients with sepsis, increased expression of miR-221 and miR-222 correlates with immunoparalysis and increased organ damage. Our results show that specific microRNAs can regulate macrophage tolerization and may serve as biomarkers of immunoparalysis and poor prognosis in patients with sepsis. The microRNAs miR-221 and miR-222 regulate the reprogramming of macrophages during the development of lipopolysaccharide tolerance, and increased expression of these microRNAs is associated with immunosuppression and poor prognosis in patients with sepsis., Author(s): John J. Seeley [sup.1] , Rebecca G. Baker [sup.1] , Ghait Mohamed [sup.2] , Tony Bruns [sup.2] [sup.3] , Matthew S. Hayden [sup.1] [sup.4] , Sachin D. Deshmukh [sup.2] [...]

Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.A genetic atlas of the human plasma proteome, comprising 1,927 genetic associations with 1,478 proteins, identifies causes of disease and potential drug targets., Author(s): Benjamin B. Sun [sup.1] , Joseph C. Maranville [sup.2] [sup.20] , James E. Peters [sup.1] [sup.3] , David Stacey [sup.1] , James R. Staley [sup.1] , James Blackshaw [sup.1] [...]

Background/objectives: The reliability of an estimate of iodine intake is largely dependent on the quality of the food composition data. We aimed to assess the impact of variations in food composition data for iodine and season on the estimates of iodine intake in young children. Subjects/methods: Cross-sectional dietary intake study of Irish 2-year-olds participating in the Cork BASELINE Birth Cohort Study (n=468; 30% of the cohort at the 2-year follow-up) were used to assess the impact of variation in iodine food composition data on estimates of iodine intake, dietary adequacy and risk of exceeding the tolerable upper intake level (UL). Results: Mean (SD) iodine intakes calculated using UK (147 (71)) and Irish (177 (93)) food composition data were significantly different (P < 0.001) (mean difference (95% confidence interval) = 30 (26-33) [micro]g/day) and largely adequate (7-14% below the estimated average requirement). Intakes at the 95th percentile were 138% and 173% of the UL using UK and Irish food composition data, respectively, of which milk accounted for 106% and 150% of the UL. This translated into 22% and 35% of toddlers exceeding the UL, using UK and Irish composition data, respectively. The mean (SD) daily intake of cow's milk among the 91% of consumers was 309 (208) ml. Intakes of cow's milk at the 75th and 95th percentiles were 452 and 706 ml, respectively. Using Irish composition data for iodine in cows' milk, a daily intake of 450 ml could result in a toddler exceeding the UL from milk alone. Conclusions: Variability in food composition has a large impact on assessments of iodine intake, particularly among young children for whom milk contributes a large proportion of their daily nutrient intake. Although this is unlikely to result in long-term adverse effects, our study highlights the need for development of valid biomarkers of individual iodine status., Author(s): Áine Hennessy [sup.1] [sup.2] , Carol ní Chaoimh [sup.1] [sup.2] , Elaine K. McCarthy [sup.1] [sup.2] , Ciara Kingston [sup.1] , Alan D. Irvine [sup.3] [sup.4] [sup.5] , Jonathan [...]

Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease. A robust signature of circulating inflammatory proteins is causally associated with 10-year risk of progression to end-stage renal disease in diabetic patients, Author(s): Monika A. Niewczas [sup.1] [sup.2] , Meda E. Pavkov [sup.3] , Jan Skupien [sup.1] [sup.4] , Adam Smiles [sup.1] , Zaipul I. Md Dom [sup.1] [sup.2] , Jonathan M. [...]

Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity. The integration of liver and plasma quantitative lipidomic and proteomic data from 107 distinct mouse strains provides important insights into regulators of mammalian lipid metabolism., Author(s): Benjamin L. Parker [sup.1] , Anna C. Calkin [sup.2] [sup.3] , Marcus M. Seldin [sup.4] , Michael F. Keating [sup.2] [sup.3] [sup.5] , Elizabeth J. Tarling [sup.6] [sup.7] , [...]

Patients with acute/critical illness are particularly vulnerable to muscle loss and fluid shifts, which adversely impact clinical outcomes. Assessment of these parameters in hospital settings is often subjective and imprecise, which creates discrepancies in identification and difficulty in assessing longitudinal changes. Body composition (BC) technologies provide objective information about muscle and fluid status that can enhance clinical assessment, and BC variables could be biomarkers for prognosis and targets to monitor intervention. There is growing interest in computed tomography (CT), ultrasound (US), and bioimpedance techniques as bedside assessment tools in clinical populations, and specific muscle measures, whole-body BC estimates, and select BC variables show promise as biomarkers of muscle health, nutrition risk, and fluid status. This brief review highlights work within the past 5 years on the use of BC variables generated from CT, US, and bioimpedance in clinical populations with an emphasis on those with acute/critical illness and a brief discussion of implementation challenges in these populations. Consensus on measurement protocols will facilitate identification of BC targets that best reflect prognosis and outcomes and will ultimately allow clinicians to identify individuals who would benefit most from targeted nutrition and physical therapy interventions and reliably monitor their response to treatment., Author(s): Kathleen L. Price [sup.1] , Carrie P. Earthman [sup.1] Author Affiliations: (1) Department of Food Science and Nutrition, University of Minnesota-Twin Cities, St Paul, USA Introduction Clinicians around the [...]

Background/objective Available data indicate a possible beneficial effect of flaxseed on cardiovascular disease, but limited studies have evaluated the effects of flaxseed on endothelial dysfunction and biomarkers of inflammation in patients with coronary artery disease (CAD). The purpose of the present study was to examine the effect of flaxseed consumption on flow-mediated dilation (FMD) and inflammatory markers in CAD patients. Subjects/method In this randomized controlled parallel trial, 50 patients with CAD of both genders were randomly allocated to 12 weeks consumption of flaxseed (30 g/day) or usual care control. Before and after the intervention, changes in brachial FMD and plasma high-sensitivity C-reactive protein (hs-CRP), interleukine-6 (IL-6), and tumor necrosis factor-[alpha] (TNF-[alpha]) were measured. Results Forty-four participants (aged 56.43 [plus or minus] 8.21 years; BMI 26.65 [plus or minus] 2.44 kg/m.sup.2) completed the study. No significant weight change was observed in either group. Compared to control (n = 23), flaxseed consumption (n = 21) was associated with improved FMD (mean of change from baseline was 5.1 vs -0.55%; p = 0.001 for the flaxseed and control, respectively). When compared to control, flaxseed consumption was associated with reduced inflammatory markers (mean of change from baseline for hs-CRP was -1.18 and -0.3 mg/L, p = 0.003; for IL-6 was -7.65 and -0.77 pg/mL, p = 0.017; for TNF-[alpha] was -34.73 and -2.18 pg/mL p = 0.001 in flaxseed and control, respectively). Conclusions The results of this study indicate that by adding flaxseed to diet of CAD patients, it is possible to improve FMD and plasma levels of inflammatory markers., Author(s): Nafiseh Khandouzi [sup.1] , Ali Zahedmehr [sup.2] , Ali Mohammadzadeh [sup.3] , Hamid Reza Sanati [sup.2] , Javad Nasrollahzadeh [sup.1] Author Affiliations: (1) Department of Clinical Nutrition & Dietetics, [...]

Background/objective Taste is of key importance in food choice and dietary patterns, but studies on taste profiles are limited. We previously assessed dietary taste patterns by 24 h recalls (24hR), but for epidemiological studies food frequency questionnaires (FFQ) may also be suitable. This study compared dietary taste patterns based on FFQ against 24hR and biomarkers of exposure. Subjects/methods A taste database including 467 foods' sweet, sour, bitter, salt, umami and fat sensation values was combined with food intake data to assess dietary taste patterns: the contribution to energy intake of 6 taste clusters. The FFQ's reliability was assessed against 3-d 24hR and urinary biomarkers for sodium (Na) and protein intake (N) in Dutch men (n = 449) and women (n = 397) from the NQplus validation study (mean age 53 [plus or minus] 11 y, BMI 26 [plus or minus] 4 kg/m.sup.2). Results Correlations of dietary taste patterns ranged from 0.39-0.68 between FFQ and 24hR (p < 0.05). Urinary Na levels, but not N levels, were positively associated with % energy intake from 'salt, umami & fat' tasting foods (Na; FFQ, r = 0.24, 24hR, r = 0.23, p < 0.001, N; FFQ, r = 0.08, p = 0.1394, 24hR, r = 0.05, p = 0.3427). Conclusions The FFQ's reliability against 24hR was acceptable to good for ranking of adults' dietary taste patterns. Associations between dietary taste patterns and urinary Na and N were similar for FFQ and 24hR. These findings suggests that both FFQ and 24hR can be used in combination with our taste database, to investigate potential relationships between dietary taste patterns and subgroups at risk of obesity and chronic diseases such as cardiovascular disease., Author(s): Astrid W. B. van Langeveld [sup.1] , Pey Sze Teo [sup.1] [sup.2] , Monica Mars [sup.1] , Edith J. M. Feskens [sup.1] , Cees de Graaf [sup.1] , Jeanne [...]

Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS. Single-cell RNA-seq of a mouse model of multiple sclerosis uncovers new oligodendrocyte populations and putative disease markers and suggests new mechanisms underlying the pathogenesis of the disease., Author(s): Ana Mendanha Falcão [sup.1] , David van Bruggen [sup.1] , Sueli Marques [sup.1] , Mandy Meijer [sup.1] , Sarah Jäkel [sup.2] , Eneritz Agirre [sup.1] , Samudyata [sup.1] , [...]

The use of liquid biopsies for cancer detection and management is rapidly gaining prominence.sup.1. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations.sup.2-5. By contrast, large-scale epigenetic alterations--which are tissue- and cancer-type specific--are not similarly constrained.sup.6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns. An immunoprecipitation-based protocol is developed to analyse DNA methylation in small quantities of circulating cell-free DNA, and can detect and classify cancers in plasma samples from several tumour types., Author(s): Shu Yi Shen [sup.1] , Rajat Singhania [sup.1] , Gordon Fehringer [sup.2] , Ankur Chakravarthy [sup.1] , Michael H. A. Roehrl [sup.1] [sup.3] [sup.4] , Dianne Chadwick [sup.1] , [...]

Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment.sup.1; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma ((https://clinicaltrials.gov/ct2/show/NCT02519322)). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers. Neoadjuvant combination treatment with nivolumab and ipilimumab in patients with high-risk melanoma results in higher response rates than nivolumab monotherapy and warrants future optimization of dosing regimens to preserve efficacy while limiting toxicity., Author(s): Rodabe N. Amaria [sup.1] , Sangeetha M. Reddy [sup.2] , Hussein A. Tawbi [sup.1] , Michael A. Davies [sup.1] , Merrick I. Ross [sup.3] , Isabella C. Glitza [sup.1] [...]

Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein-Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein-Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value [greater than or equal to]1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(-) tumors (50.0% versus 0.0%, P value Microsatellite instability and Epstein-Barr virus positivity represent novel biomarkers of clinical response to PD-1 blockade in patients with metastatic gastric cancer., Author(s): Seung Tae Kim [sup.1] , Razvan Cristescu [sup.2] , Adam J. Bass [sup.3] , Kyoung-Mee Kim [sup.4] , Justin I. Odegaard [sup.5] , Kyung Kim [sup.1] , Xiao Qiao [...]

Cellular transformation is accompanied by extensive rewiring of many biological processes leading to augmented levels of distinct types of cellular stress, including proteotoxic stress. Cancer cells critically depend on stress-relief pathways for their survival. However, the mechanisms underlying the transcriptional initiation and maintenance of the oncogenic stress response remain elusive. Here, we show that the expression of heat shock transcription factor 1 (HSF1) and the downstream mediators of the heat shock response is transcriptionally upregulated in T cell acute lymphoblastic leukemia (T-ALL). Hsf1 ablation suppresses the growth of human T-ALL and eradicates leukemia in mouse models of T-ALL, while sparing normal hematopoiesis. HSF1 drives a compact transcriptional program and among the direct HSF1 targets, specific chaperones and co-chaperones mediate its critical role in T-ALL. Notably, we demonstrate that the central T-ALL oncogene NOTCH1 hijacks the cellular stress response machinery by inducing the expression of HSF1 and its downstream effectors. The NOTCH1 signaling status controls the levels of chaperone/co-chaperone complexes and predicts the response of T-ALL patient samples to HSP90 inhibition. Our data demonstrate an integral crosstalk between mediators of oncogene and non-oncogene addiction and reveal critical nodes of the heat shock response pathway that can be targeted therapeutically. Oncogenic NOTCH1 controls transcriptional activation of the heat shock response in T cell acute lymphoblastic leukemia and uncovers potential biomarkers of sensitivity to HSP90 inhibition., Author(s): Nikos Kourtis [sup.1] , Charalampos Lazaris [sup.1] , Kathryn Hockemeyer [sup.1] , Juan Carlos Balandrán [sup.2] [sup.3] [sup.4] , Alejandra R. Jimenez [sup.4] , Jasper Mullenders [sup.1] [sup.10] , [...]

Background/objectives Studies of the effect of vitamin B12 and folate on the risk of asthma and hay fever have shown inconsistent results that may be biased by reverse causation and confounding. We used a Mendelian randomization approach to examine a potential causal effect of vitamin B12 and folate on hay fever, asthma, and selected biomarkers of allergy by using 11 vitamin B12-associated single-nucleotide polymorphisms (SNPs) and 2 folate-associated SNPs as unconfounded markers. Subjects/methods We included 162,736 participants from 9 population-based studies including the UK Biobank. Results were combined in instrumental variable and meta-analyses and effects expressed as odds ratios (ORs) or estimates with 95% confidence interval (CI). Results Using genetic proxies for B12 and folate, instrumental variable analyses did not show evidence for associations between serum B12 and hay fever: OR = 1.02 (95% CI: 0.98, 1.05), asthma: OR = 0.99 (95% CI: 0.95, 1.04), allergic sensitization: OR = 1.02 (95% CI: 0.74, 1.40), or change in serum IgE: 10.0% (95% CI: -9.6%, 29.6%) per 100 pg/ml B12. Similarly, there was no evidence for association between serum folate and hay fever: OR = 0.74 (95% CI: 0.45, 1.21), asthma: OR = 0.80 (95% CI: 0.43, 1.49), or allergic sensitization: OR = 1.92 (95% CI: 0.11, 33.45), but there was a statistically significant association with change in serum IgE: 2.0% (95% CI: 0.43%, 3.58%) per 0.1 ng/ml serum folate. Conclusions Our results did not support the hypothesis that levels of vitamin B12 and folate are causally related to hay fever, asthma, or biomarkers of allergy, but we found evidence of a positive association between serum folate and serum total IgE., Author(s): Tea Skaaby [sup.1] , Amy E. Taylor [sup.2] [sup.3] , Rikke K. Jacobsen [sup.1] , Line T. Møllehave [sup.1] , Nele Friedrich [sup.1] [sup.4] , Betina H. Thuesen [sup.1] [...]

Objective: To investigate the effects of increasing Cu intakes, above the usual dietary intake, on biomarkers of bone metabolism in healthy young adult females (aged 21-28y) over a 4 week period. Design: A double-blind, placebo-controlled randomised repeat crossover Cu supplementation trial. Setting: The study was conducted at the Royal Veterinary and Agricultural University (RVAU), Copenhagen, Denmark. Subjects: Sixteen healthy young adult females aged 20-28 y were recruited from among students at the RVAU. Intervention: During the 4 week intervention periods in this randomised, crossover trial (3x4 weeks with a minimum 3 week wash-out period), each subject received, in addition to their usual diet, either 3 or 6 mg elemental Cu/day as CuS[O.sub.4] or a matching placebo. On the last 3 days of each dietary period 24h urines were collected. In addition, blood was collected on the last day of each dietary period. Results: Serum Cu and erythrocyte superoxide dismutase (but not caeruloplasmin protein concentration or activity (putative indices of Cu status)) were significantly increased (P < 0.05) after daily Cu supplementation with 3 and 6 mg/day for 4 weeks. Serum osteocalcin (biomarker of bone formation), urinary creatinine (Cr) concentration, urinary pyridinoline (Pyr)/Cr or deoxypyridinoline (Dpyr)/Cr excretion, or daily urinary Pyr or Dpyr excretion (biomarkers of bone resorption) were unaffected by Cu supplementation. Conclusion: Copper supplementation of the usual diet in healthy young adult females, while apparently improving Cu status, had no effect on biochemical markers of bone formation or bone resorption over 4 week periods. Sponsorship: Funding from the European Commission. Descriptors: copper status; bone; biomarkers; young adult females, Introduction Copper has an important role in the metabolism of the skeleton, where it performs a key catalytic function as a cofactor for lysyl oxidase (E.C. 1.4.3.13), a Cu-dependent extracellular [...]

Author(s): Javier Carmona [sup.1] Author Affiliations: (1) Nature Medicine, Science 362 , eaar3593 (2018). In combination, tumor mutational burden and the immunological state of the tumor microenvironment predict clinical responses [...]

Objective:: This study examined the interaction between body mass index (BMI) and attempting to lose weight for reporting of: (1) macro- and micronutrient intake; (2) intake of low-nutrient-density foods; and (3) serum biomarkers of dietary exposure and cardiovascular disease risk. Methods:: Dietary, anthropometric and biochemical data were from the third National Health and Nutrition Examination Survey (1988-1994), n=13[??]095. Multiple regression methods were used to examine the independent associations of BMI, trying to lose weight, or the interaction of BMI-trying to lose weight with reported intakes of energy, nutrients, percentage energy from low-nutrient-density foods (sweeteners, baked and dairy desserts, visible fats and salty snacks), and serum concentrations of vitamins, carotenoids and lipids. Results:: BMI was an independent positive predictor (P [less than] 0.05) of percentage of energy from fat, saturated fat, but a negative predictor of the ratio of reported energy intake to estimated expenditure for basal needs (EI/BEE), percentage of energy from carbohydrate and alcohol (men only), and serum concentrations of folate, vitamin C, vitamin E and most carotenoids in both men and women. Trying to lose weight was a negative predictor (P [less than] 0.05) of EI/BEE, intake of energy, and energy density, but not micronutrient intake. Higher mean serum ascorbate, vitamin E, lutein/zeaxanthin, and other carotenoids (men only) concentrations were associated with trying to lose weight (P [less than] 0.05) in both men and women. Few adverse BMI-trying to lose weight interaction effects were noted. Conclusion:: There was little evidence of increased nutritional risk in those reportedly trying to lose weight irrespective of weight status. Sponsorship:: NIH research grant (R03 CA81604) and a USDA NRICGP award (NYR-9700611). European Journal of Clinical Nutrition (2003) 57, 249-259. doi: 10.1038/sj.ejcn.1601549 Keywords: weight loss, dieting, junk food intake, low-nutrient-density foods, dietary patterns, serum vitamins, serum carotenoids, serum lipids, NHANES III, Author(s): A K Kant [1] Introduction Increasing prevalence of obesity is a global public health problem, and weight control is recommended to alleviate the health risks associated with adiposity (WHO, [...]