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The impact of integrase inhibitor-based regimens on markers of inflammation among HIV naïve patients.
Quiros-Roldan, E, Castelli, F, Bonito, A, Vezzoli, M, Calza, S, Biasiotto, G, Zanella, I, ,
Cytokine. 2020;:154884
Abstract
The use of combination anti-retroviral therapy (cART) correlates with longer and healthier life and with nearly normal life expectancy in people living with HIV. However, cART does not completely restore health. Chronic immune activation and inflammation persist in treated patients and have been described as predictors for clinical events and mortality in HIV-infected patients. Limited information is available on the impact of the various cART regimens on inflammation/immunoactivation. The aim of this work was to explore the impact of elvitegravir, dolutegravir, raltegravir (integrase strand transfer inhibitors, INSTIs) and atazanavir (protease inhibitor, PI) on several soluble markers of immune activation and inflammation during the first year of effective combination anti-retroviral therapy (cART). We conducted an observational retrospective cohort study in HIV-infected cART-naïve patients who initiated an INSTI or atazanavir regimen between March 2015 and February 2016 and a serum sample was available at baseline, 6 and 12 months after initiation. We compared the trend of D-Dimer, TNF- α, IL-2, IL-6, IL-7, IL-10, CCL4/MIP1-β, CCL5/RANTES, s-CD14, s-CD163, hs-CRP levels among the 4 arms of treatment. Percentage of variation from baseline was also measured for all markers. A total of 36 patients were included. We observed heterogeneous modifications in inflammation markers among arms. In particular, we noted that EVG have significant negative effect on s-CD14, hs-CRP, IL-6 and D-Dimer in respect to other INSTIs and this different effect occurs mainly during the first 6 months of cART. IL-7 values increased in the three arms with INSTIs (significantly only in EGV, 159.8%, p = 0.0003) and decreased significantly in patients on PI (-48.96%; p = 0.04) over the period. In conclusion, our results provide further data on changes of inflammatory marker levels, especially for the new INSTIs. Our data show that among INSTIs, EVG seems to have a worse impact on inflammation.
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Genetic determinants of the humoral immune response in MS.
Gasperi, C, Andlauer, TFM, Keating, A, Knier, B, Klein, A, Pernpeintner, V, Lichtner, P, Gold, R, Zipp, F, Then Bergh, F, et al
Neurology(R) neuroimmunology & neuroinflammation. 2020;(5)
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OBJECTIVE In this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS). METHODS Using regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively. RESULTS The minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (β = 0.58 [0.47 to 0.68], lowest adjusted p = 2.32 × 10-23), and lower intrathecal immunoglobulin M (β = -0.56 [-0.67 to -0.46], p = 2.06 × 10-24) and A (β = -0.42 [-0.54 to -0.31], p = 7.48 × 10-11) levels. Alleles from the HLA-B*07:02-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype were associated with higher (lowest p = 2.14 × 10-7) and HLA-B*44:02 with lower (β = -0.35 [-0.54 to -0.17], p = 1.38 × 10-2) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, β = -0.45 [-0.61 to -0.28], p = 1.01 × 10-5) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], p = 4.46 × 10-3). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts. CONCLUSION Although some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms.
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Sex-Specific Regulation of Inflammation and Metabolic Syndrome in Obesity.
Ter Horst, R, van den Munckhof, ICL, Schraa, K, Aguirre-Gamboa, R, Jaeger, M, Smeekens, SP, Brand, T, Lemmers, H, Dijkstra, H, Galesloot, TE, et al
Arteriosclerosis, thrombosis, and vascular biology. 2020;(7):1787-1800
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OBJECTIVE Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity. Approach and Results: Three hundred two individuals were included, half with a BMI 27 to 30 kg/m2 and half with a BMI>30 kg/m2, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed. Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and men: women with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity. CONCLUSIONS We identified sex-specific pathways that influence inflammation in obesity. Excessive production of proinflammatory cytokines was observed in men with metabolic syndrome. In contrast, women typically showed reduced levels of the anti-inflammatory adipokine adiponectin. These different mechanisms of inflammatory dysregulation between women and men with obesity argue for sex-specific therapeutic strategies.
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Dissecting the heterogeneity of the alternative polyadenylation profiles in triple-negative breast cancers.
Wang, L, Lang, GT, Xue, MZ, Yang, L, Chen, L, Yao, L, Li, XG, Wang, P, Hu, X, Shao, ZM
Theranostics. 2020;(23):10531-10547
Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive malignancy with high heterogeneity. However, the alternative polyadenylation (APA) profiles of TNBC remain unknown. Here, we aimed to define the characteristics of the APA events at post-transcription level among TNBCs. Methods: Using transcriptome microarray data, we analyzed APA profiles of 165 TNBC samples and 33 paired normal tissues. A pooled short hairpin RNA screen targeting 23 core cleavage and polyadenylation (C/P) genes was used to identify key C/P factors. Results: We established an unconventional APA subtyping system composed of four stable subtypes: 1) luminal androgen receptor (LAR), 2) mesenchymal-like immune-activated (MLIA), 3) basal-like (BL), 4) suppressed (S) subtypes. Patients in the S subtype had the worst disease-free survival comparing to other patients (log-rank p = 0.021). Enriched clinically actionable pathways and putative therapeutic APA events were analyzed among each APA subtype. Furthermore, CPSF1 and PABPN1 were identified as the master C/P factors in regulating APA events and TNBC proliferation. The depletion of CPSF1 or PABPN1 weakened cell proliferation, enhanced apoptosis, resulted in cell cycle redistribution and a reversion of APA events of genes associated with tumorigenesis, proliferation, metastasis and chemosensitivity in breast cancer. Conclusions: Our findings advance the understanding of tumor heterogeneity regulation in APA and yield new insights into therapeutic target identification in TNBC.
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Vitamin D deficiency as the risk of respiratory tract infections in the institutionalized elderly: A prospective 1-year cohort study.
Kuwabara, A, Tsugawa, N, Ao, M, Ohta, J, Tanaka, K
Clinical nutrition ESPEN. 2020;:309-313
Abstract
BACKGROUND & AIMS Respiratory tract infections (RTIs) are one of the major causes of morbidity and mortality in the elderly. Since vitamin D is known to play important roles in immunity, and its deficiency has been reported to be prevalent in the elderly, we have studied the relationship between serum 25-hydroxyvitamin D [25(OH)D] level, which is the most reliable marker for vitamin D status, and the incidence of RTIs in the institutionalized elderly by a prospective observational study. METHODS From 208 Japanese subjects aged 60 and older fulfilling the inclusion criteria, 148 subjects remained after propensity score matching. Data were obtained from the medical records including their age, gender, histories of co-morbidities and medications, the incidence of acute RTIs including pneumonia. Measurement of serum 25(OH)D level and assessment of nutrients intake including vitamin D were done at baseline. Cox's proportional hazard analysis was performed to assess the significant predictors for RTIs during the follow-up period. RESULTS The median observation duration was 354.2 days, and the incidence of RTIs was 75.8 person-years. Subjects with RTIs had significantly lower serum 25(OH)D concentration, and a higher prevalence of vitamin D deficiency (25(OH)D < 10 ng/mL). Cox's proportional hazard analysis revealed that vitamin D deficiency was a significant predictor for RTIs. CONCLUSIONS Our results suggested that vitamin D deficiency was a significant predictor for an increased incidence of RTIs in institutionalized elderly, and the necessity of vitamin D supplementation for the prevention of RTIs was considered.
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Fat mass affects nutritional status of ICU COVID-19 patients.
De Lorenzo, A, Tarsitano, MG, Falcone, C, Di Renzo, L, Romano, L, Macheda, S, Ferrarelli, A, Labate, D, Tescione, M, Bilotta, F, et al
Journal of translational medicine. 2020;(1):299
Abstract
BACKGROUND Obesity and steatosis are associated with COVID-19 severe pneumonia. Elevated levels of pro-inflammatory cytokines and reduced immune response are typical of these patients. In particular, adipose tissue is the organ playing the crucial role. So, it is necessary to evaluate fat mass and not simpler body mass index (BMI), because BMI leaves a portion of the obese population unrecognized. The aim is to evaluate the relationship between Percentage of Fat Mass (FM%) and immune-inflammatory response, after 10 days in Intensive Care Unit (ICU). METHODS Prospective observational study of 22 adult patients, affected by COVID-19 pneumonia and admitted to the ICU and classified in two sets: (10) lean and (12) obese, according to FM% and age (De Lorenzo classification). Patients were analyzed at admission in ICU and at 10th day. RESULTS Obese have steatosis, impaired hepatic function, compromise immune response and higher inflammation. In addition, they have a reduced prognostic nutritional index (PNI), nutritional survival index for ICU patients. CONCLUSION This is the first study evaluating FM% in COVID-19 patient. We underlined obese characteristic with likely poorly prognosis and an important misclassification of obesity. A not negligible number of patients with normal BMI could actually have an excess of adipose tissue and therefore have an unfavorable outcome such as an obese. Is fundamental personalized patients nutrition basing on disease phases.
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Cytokine release after gluten ingestion differentiates coeliac disease from self-reported gluten sensitivity.
Tye-Din, JA, Skodje, GI, Sarna, VK, Dzuris, JL, Russell, AK, Goel, G, Wang, S, Goldstein, KE, Williams, LJ, Sollid, LM, et al
United European gastroenterology journal. 2020;(1):108-118
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BACKGROUND Diagnosing coeliac disease (CD) in patients on a gluten-free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)-2, IL-8 and IL-10 in CD patients on a GFD. OBJECTIVE We tested whether cytokine release after gluten ingestion differentiates patients with CD from those with self-reported gluten sensitivity (SR-GS). METHODS Australian patients with CD (n = 26) and SR-GS (n = 18) on a GFD consumed bread (estimated gluten 6 g). Serum at baseline and at 3 and 4 h was tested for IL-2, IL-8 and IL-10. Separately, Norwegian SR-GS patients (n = 49) had plasma cytokine assessment at baseline and at 2, 4 and 6 h after food bars containing gluten (5.7 g), fructan or placebo in a previous double-blind crossover study. RESULTS Gluten significantly elevated serum IL-2, IL-8 and IL-10 at 3 and 4 h in patients with CD but not SR-GS. The highest median fold-change from baseline at 4 h was for IL-2 (8.06, IQR: 1.52-24.0; P < 0.0001, Wilcoxon test). The two SR-GS cohorts included only one (1.5%) confirmed IL-2 responder, and cytokine responses to fructan and placebo were no different to gluten. Overall, cytokine release after gluten was present in 22 (85%) CD participants, but 2 of the 4 non-responders remained clinically well after 1 y on an unrestricted diet. Hence, cytokine release occurred in 22 (92%) of 24 'verified' CD participants. CONCLUSIONS Gluten challenge with high-sensitivity cytokine assessment differentiates CD from SR-GS in patients on a GFD and identifies patients likely to tolerate gluten reintroduction. Systemic cytokine release indicating early immune activation by gluten in CD individuals cannot be detected in SR-GS individuals.
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Analyses of Programmed Cell Death Protein 1 in High Immunologic-Risk Transplant Patients.
Carmona-Escamilla, MA, Fonseca-Sánchez, MÁ, Chávez, JP, Pizando, LA, Soto, V, Hernández-Mendoza, SA, García-Covarrubias, L, Queipo, G
Transplantation proceedings. 2020;(4):1132-1135
Abstract
Kidney transplant (KT) is the first therapeutic option for most patients with chronic renal failure that requires renal function replacement. The main complication associated with renal graft loss is immune rejection. The T regulatory pathways play a key role in this process, and abnormalities in some of these molecules could participate in the graft rejection. In this paper, our group performed an exploratory analysis of the behavior of the coinducible molecules (CD28, CTLA-4, ICOS, PD-1) in patients with KT rejection and control KT patients without rejection. The Mann-Whitney U test, used for 2 groups, showed significant differences (P = .0005), indicating that PD-1 is underexpressed in patients with allograft rejection. No differences were found in CD28+, regulatory T cells (T reg), CTLA-4, and ICOS, so we are proposing that PD-1 is a key player in the immunotolerance phenomenon and its underexpression participates in the rejection process. More research needs to be performed on this topic.
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Study of the fetal and maternal microbiota in pregnant women with intrauterine growth restriction and its relationship with inflammatory biomarkers: A case-control study protocol (SPIRIT compliant).
Fernandez-Gonzalez, S, Ortiz-Arrabal, O, Torrecillas, A, Pérez-Cruz, M, Chueca, N, Gómez-Roig, MD, Gómez-Llorente, C
Medicine. 2020;(46):e22722
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In general terms, fetal growth restriction (FGR) is considered the impossibility of achieving the genetically determined potential size. In the vast majority of cases, it is related to uteroplacental insufficiency. Although its origin remains unknown and causes are only known in 30% of cases, it is believed to be related to an interaction of environmental and genetic factors with either a fetal or maternal origin. One hypothesis is that alterations in the gastrointestinal microbiota composition, and thus alteration in the immune response, could play a role in FGR development. We performed an observational, prospective study in a subpopulation affected with FGR to elucidate the implications of this microbiota on the FGR condition.A total of 63 fetuses with FGR diagnosed in the third trimester as defined by the Delphi consensus, and 63 fetuses with fetal growth appropriate for gestational age will be recruited. Obstetric and nutritional information will be registered by means of specific questionnaires. We will collect maternal fecal samples between 30 to 36 weeks, intrapartum samples (maternal feces, maternal and cord blood) and postpartum samples (meconium and new-born feces at 6 weeks of life). Samples will be analyzed in the Department of Biochemistry and Molecular Biology II, Nutrition and Food Technology Institute of the University of Granada (UGR), for the determination of the gastrointestinal microbiota composition and its relationship with inflammatory biomarkers.This study will contribute to a better understanding of the influence of gastrointestinal microbiota and related inflammatory biomarkers in the development of FGR.Trial registration: NCT04047966. Registered August 7, 2019, during the recruitment stage. Retrospectively registered. Ongoing research.
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Factors Influencing Growth of Children Aged 12-24 Months in the Tanga Region, Tanzania.
Elverud, IS, Størdal, K, Chiduo, M, Klingenberg, C
Journal of tropical pediatrics. 2020;(2):210-217
Abstract
BACKGROUND The first 1000 days of life, from conception to the second birthday, offer a unique window of opportunity for optimal growth, critical for future health. The primary aim of this study was to analyze growth of children between 12 and 24 months age in Tanzanian children, and to explore possible predictors for growth. METHODS Observational, cross-sectional study performed between March and April 2017. Eligible children, and their mothers, attended routine follow-up at two health clinics in Tanga, Tanzania. At the study day, the child's weight and height were recorded. The mothers answered a structured interview regarding breastfeeding, immunization and socioeconomic conditions. RESULTS We recruited 300 mother-child pairs. Median [interquartile range (IQR)] age at study visit was 16 (14-20) months. Mothers reported that 170 (57%) of their children were exclusively breastfed for a minimum of 6 months; median (IQR) 6 (4-6) months. Using the World Health Organization (WHO) standard growth curves, mean weight-for-age Z-score was -0.30 and mean length-for-age Z-score was -0.47. Children whose mothers had higher education had higher Z-scores for weight and length compared to children of mothers with lower education. Education remained the most important predictor for growth also after adjusting for other variables. Overall, 48/300 (16%) were moderate-severe stunted and 25/300 (8.4%) had moderate-severe underweight. CONCLUSION Children aged 12-24 months in this region of Tanzania had weight and height below the WHO standard. Higher educated mothers had children with better growth parameters. Duration of exclusive breastfeeding was long, but did not predict growth parameters.