An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study).

BACKGROUND & AIMS: It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). OBJECTIVE: To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. PATIENTS AND METHODS: In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. RESULTS: It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. CONCLUSIONS: Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.

Unlocking New Avenues in Breast Cancer Treatment: The Synergy of Kinase Inhibitors and Immunotherapy.

Cancer is one of the world's most significant health problems today. Currently, breast cancer has globally surpassed lung cancer as the most commonly diagnosed cancer in women. In 2020, an estimated 2,261,419 new cases were diagnosed in women worldwide. Therefore, there is a need to understand the processes that can help us better treat this disease. In recent years, research in the fight against cancer has often been based on two treatment modalities. One of them is the use of protein kinase inhibitors, which have been instrumental in the development of new therapeutic strategies. Another crucial route is the use of immunotherapy, which has been touted as a great promise for cancer treatment. Protein kinase alterations can interfere with the effectiveness of other treatments, such as immunotherapy. In this review, we will analyze the role played by protein kinase alterations in breast cancer and their possible impact on the effectiveness of the response to immunotherapy treatments.

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer's Disease.

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer's disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aß1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin's effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.

A metagenome-wide association study of HIV disease progression in HIV controllers.

Some HIV controllers experience immunologic progression with CD4+ T cell decline. We aimed to identify genetic factors associated with CD4+ T cell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

Characteristics and outcomes of the Spanish registry for pediatric patients with bicuspid aortic valve (REVAB).

INTRODUCTION AND OBJECTIVES: Bicuspid aortic valve (BAV) disorder is the most common congenital heart disease. The aim of this study was to describe the characteristics of 0- to 18-year olds with BAV in a population-based registry. METHODS: Data from all pediatric patients were obtained from the Spanish registry for pediatric patients with bicuspid aortic valve (REVAB) (< 18 years). For data analysis, patients with BAV were divided into 2 groups by their features: isolated BAV and BAV with associated congenital heart disease. RESULTS: We included 1681 patients from 33 hospitals. Males accounted for 69.6% (n = 1158). Valve morphology was horizontal in 63.4% (n = 1012) and pure (Sievers type 0) in 28.4% (n=469). Isolated BAV was present in 63.7% (n=1060), and concomitant left-sided obstructive lesions in 23.4% (n=390). Interventions were required in 8.6% (n=145). CONCLUSION: These data represent the first large, population-based description of the clinical presentations and outcomes of patients enrolled in the Spanish registry for pediatric patients with bicuspid aortic valve.

Proton Pump Inhibitors and the Risk of Early Aseptic Loosening in Hip and Knee Arthroplasty.

Introduction: The use of proton pump inhibitors (PPIs) has been associated with a higher risk of osteoporotic fractures and non-unions rates. However, the relation between the use of PPIs and the development of aseptic loosening in arthroplasty procedures has not been studied. The objective of this study is to analyze the relation between the use of PPIs, and the risk of early aseptic loosening in total knee arthroplasty (TKA) and total hip arthroplasty (THA). Materials and methods: A nested case-control study was conducted on patients who were subjected THA or TKA in our center between 2010 and 2014. Cases were patients subjected to revision surgery due to early aseptic loosening during the study period. Cases were matched with controls who did not require any type of revision surgery by type of joint replacement (THA/TKA), gender, age (+/- 2 years), and follow-up time (±6 months). Odds Ratios were adjusted to potential confounders. Results: The crude and adjusted ORs (95% CI) of undergoing revision surgery for aseptic loosening following primary total knee arthroplasty or total hip arthroplasty, were 6.25 (2.04-19.23) and 6.10 (1.71-21.73), respectively, for any use PPIs compared with non-users. Crude and adjusted ORs, were 11.6 (2.93-45.88) and 17.1 (2.41-121.66), respectively, for patients with a Proportion of Days Covered (PDC) for PPIs <.5 (Table 2). In addition, the crude and adjusted ORs of undergoing revision surgery, were 5.05 (1.59-16.02) and 5.01 (1.36-18.44), respectively, for patients with a PDC for PPIs ≥.5. Discussion: These results suggest that PPIs should be used with caution in patients with TKA and THA, and that the use of these drugs should not be prolonged unless there was a justifiable indication. Conclusions: The use of PPIs and was associated with a higher risk of early aseptic loosening in patients subjected to THA and TKA.

Changes in pulmonary and plasma oxidative stress and inflammation following eccentric and concentric cycling in stable COPD patients.

PURPOSE: The purpose of this study was to compare pulmonary and plasma markers of oxidative stress and inflammation after concentric and eccentric cycling bouts in individuals with chronic obstructive pulmonary disease (COPD). METHODS: Ten patients with moderate COPD level (68.3 ± 9.1 years; forced expiratory volume in 1 s = 68.6 ± 20.4% of predicted) performed 30 min of moderate-intensity concentric (CONC-M: 50% maximum concentric cycling power output; POmax) and eccentric cycling (ECC-M: 50% POmax), and high-intensity eccentric cycling (ECC-H: 100% POmax) in a randomised order. Cardiometabolic demand was monitored during cycling. Indirect markers of muscle damage were assessed before, immediately after, 24 and 48 h after cycling (muscle strength, muscle soreness and creatine kinase activity). Plasma oxidative stress (malondialdehyde: MDA), antioxidant (glutathione peroxidase activity: GPx) and inflammatory markers (IL-6, TNF-α) were measured before and 5 min after cycling. Exhaled breath condensate (EBC) samples were collected before and 15 min after cycling and analysed for hydrogen peroxide (H2O2), nitrites (NO2-) and pH. RESULTS: Cardiometabolic demand was 40-50% lesser for ECC-M than CONC-M and ECC-H. Greater muscle damage was induced after ECC-H than ECC-M and CONC-M. MDA decreased immediately after CONC-M (- 28%), ECC-M (- 14%), and ECC-H (- 17%), while GPx remained unchanged. IL-6 increased only after ECC-H (28%), while TNF-α remained unchanged after exercise. Pulmonary H2O2, NO2- and pH remained unchanged after exercise. CONCLUSION: These results suggest that only moderate muscle damage and inflammation were induced after high-intensity eccentric cycling, which did not induce pulmonary or plasmatic increases in markers of oxidative stress. TRIAL REGISTRATION NUMBER: Trial registration number: DRKS00009755.

Toll-Like Receptor 2 Promoter -196 to -174 Deletion Affects CD4 Levels Along Human Immunodeficiency Virus Infection Progression.

Toll-like receptor 2 (TLR2) plays a key role in innate immune response recognizing molecular patterns expressed by pathogens. rs111200466 is a TLR2 promoter insertion/deletion polymorphism with contradictory data about its role in human immunodeficiency virus type 1 (HIV-1) infection. We analyzed rs111200466 in HIV-1 disease progression and showed a correlation with a faster progression to the CD4+ < 200 cells/µL outcome for deletion allele carriers (Cox regression analysis: hazard ratio, 2.4 [95% confidence interval, 1.4-4]; P = .001). When naive patients with CD4+ < 200 cells/µL started antiretroviral treatment, rs111200466-deletion carriers showed a trend toward a slower, recovery rate (time required to reach CD4+ > 350 cells/µL; Cox P = .36). Our data suggest rs111200466 as a prognosis factor for HIV-1 disease progression.

Risk of stroke in prescription and other amphetamine-type stimulants use: A systematic review.

INTRODUCTION AND AIMS: Amphetamine-type stimulants (ATS) are a putative cause of stroke with high abuse potential. We aim to systematically review the association between use of ATS and stroke. DESIGN AND METHODS: To assure a sensitive search strategy, a broad definition of ATS was used. Cochrane Plus, EMBASE, IBECS/Lilacs, ISI WOK, Medline and Scopus were searched through 2016. Three researchers independently reviewed studies (Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-analyses). Validity and bias were appraised. RESULTS: Of 3998 articles, four cohort studies and eight case-control studies (CCS) were selected; 11 focused on prescribed or over-the-counter ATS. Current ATS users showed a higher ischaemic stroke risk than non-users in two cohort studies {adjusted rate ratio = 1.6 [95% confidence interval (CI) = 1.1, 2.4] and 3.4 [95% CI = 1.1, 10.6]}. One study observed increased risk of haemorrhagic stroke in former users versus non-users [adjusted rate ratio = 2.3 (95% CI = 1.3, 4.1)]. Higher haemorrhagic stroke risk was seen in two CCS among women using ATS [adjusted odds ratio (aOR) = 16.6 (95% CI = 1.5, 182.2) and 3.9 (95% CI = 1.1, 13.1)]. All-stroke was negatively associated with ATS in another CCS [aOR = 0.4 (95% CI = 0.2, 0.8)] and positively associated in the only study on non-medical ATS [aOR = 3.8 (95% CI = 1.2, 12.6)]. Selection bias and uncontrolled confounding were common. DISCUSSION AND CONCLUSIONS: This is the first systematic review on ATS and stroke. Limited epidemiological evidence suggests that ATS use increases stroke risk. Possible disparities in ATS effect across stroke type and higher effect in women deserve further clarification. Studies on non-medical ATS use should be a priority. [Indave BI, Sordo L, Bravo MJ, Sarasa-Renedo A, Fernández-Balbuena S, De la Fuente L, Sonego M, Barrio G. Risk of stroke in prescription and other amphetamine-type stimulants use: A systematic review. Drug Alcohol Rev 2018;37:56-69].

De novo recipient-specific Glutathione S-transferase T1 antibody development after HLA-identical hematopoietic cell transplantation.

Donor-specific antibodies against Glutathione S-transferase T1 (GSTT1) have been associated with de novo immune hepatitis after liver transplantation. These antibodies have also been found very early in allo-HCT associated with acute hepatic GvHD but in all the cases the donor cells had experienced previous priming through pregnancies. It remained to be explored whether or not primary recognition of the antigen occurs after HCT and what could be the consequences in the long term outcome. We genotyped a cohort of 68 HCT patients and found 11 with the GSTT1 null donor/positive recipient mismatch. After testing 114 serum samples, we found a unique case of a 33-year-old patient transplanted from his HLA-identical sibling donor in which IgG GSTT1 antibodies were detected for the first time on day +178. After stimulation of peripheral blood mononuclear cells with GSTT1 peptides we could demonstrate that this patient also had GSTT1-specific T lymphocytes that became activated upon exposure to the GSTT1 antigen. In this report, we describe the first case in which simultaneous T and B cell response against GSTT1 is developed in HCT although the clinical consequences in GvHD are still unclear.

T-cell allorecognition of donor glutathione S-transferase T1 in plasma cell-rich rejection.

AIM: To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts. METHODS: The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1 (GSTT1) alleles (don+/rec-), and 4 were matched (don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection (former de novo immune hepatitis). For the detection of specific T lymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ. RESULTS: Activation of CD8+ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection (3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4+ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides (1.45%-5.18%). Highly unexpected was the finding of a double positive CD4+CD8low T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4+CD8low cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides. CONCLUSION: Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.

[Contextual indicators to assess social determinants of health and the Spanish economic recession]. / Indicadores contextuales para evaluar los determinantes sociales de la salud y la crisis económica española.

OBJECTIVE: To provide indicators to assess the impact on health, its social determinants and health inequalities from a social context and the recent economic recession in Spain and its autonomous regions. METHODS: Based on the Spanish conceptual framework for determinants of social inequalities in health, we identified indicators sequentially from key documents, Web of Science, and organisations with official statistics. The information collected resulted in a large directory of indicators which was reviewed by an expert panel. We then selected a set of these indicators according to geographical (availability of data according to autonomous regions) and temporal (from at least 2006 to 2012) criteria. RESULTS: We identified 203 contextual indicators related to social determinants of health and selected 96 (47%) based on the above criteria; 16% of the identified indicators did not satisfy the geographical criteria and 35% did not satisfy the temporal criteria. At least 80% of the indicators related to dependence and healthcare services were excluded. The final selection of indicators covered all areas for social determinants of health, and 62% of these were not available on the Internet. Around 40% of the indicators were extracted from sources related to the Spanish Statistics Institute. CONCLUSIONS: We have provided an extensive directory of contextual indicators on social determinants of health and a database to facilitate assessment of the impact of the economic recession on health and health inequalities in Spain and its autonomous regions.

Pulmonary sarcoidosis is associated with exosomal vitamin D-binding protein and inflammatory molecules.

BACKGROUND: Sarcoidosis is an inflammatory granulomatous disorder characterized by accumulation of TH1-type CD4+ T cells and immune effector cells within affected organs, most frequently the lungs. Exosomes are extracellular vesicles conveying intercellular communication with possible diagnostic and therapeutic applications. OBJECTIVES: We aimed to provide an understanding of the proinflammatory role of bronchoalveolar lavage fluid (BALF) exosomes in patients with sarcoidosis and to find candidates for disease biomarkers. METHODS: We performed a mass spectrometric proteomics characterization of BALF exosomes from 15 patients with sarcoidosis and 5 healthy control subjects and verified the most interesting results with flow cytometry, ELISA, and Western blot analyses in an additional 39 patients and 22 control subjects. RESULTS: More than 690 proteins were identified in the BALF exosomes, several of which displayed significant upregulation in patients, including inflammation-associated proteins, such as leukotriene A4 hydrolase. Most of the complement-activating factors were upregulated, whereas the complement regulator CD55 was seen less in patients compared with healthy control subjects. In addition, for the first time, we detected vitamin D-binding protein in BALF exosomes, which was more abundant in patients. To evaluate exosome-associated vitamin D-binding protein as a biomarker for sarcoidosis, we investigated plasma exosomes from 23 patients and 11 healthy control subjects and found significantly higher expression in patients. CONCLUSION: Together, these data contribute to understanding the role of exosomes in lung disease and provide suggestions for highly warranted sarcoidosis biomarkers. Furthermore, the validation of an exosome-associated biomarker in the blood of patients provides novel, and less invasive, opportunities for disease diagnosis.

Exosomal cancer immunotherapy is independent of MHC molecules on exosomes.

Peptide-loaded exosomes are promising cancer treatment vehicles; however, moderate T cell responses in human clinical trials indicate a need to further understand exosome-induced immunity. We previously demonstrated that antigen-loaded exosomes carry whole protein antigens and require B cells for inducing antigen-specific T cells. Therefore, we investigated the relative importance of exosomal major histocompatibility complex (MHC) class I for the induction of antigen-specific T cell responses and tumour protection. We show that ovalbumin-loaded dendritic cell-derived exosomes from MHCI-/- mice induce antigen-specific T cells at the same magnitude as wild type exosomes. Furthermore, exosomes lacking MHC class I, as well as exosomes with both MHC class I and II mismatch, induced tumour infiltrating T cells and increased overall survival to the same extent as syngeneic exosomes in B16 melanoma. In conclusion, T cell responses are independent of exosomal MHC/peptide complexes if whole antigen is present. This establishes the prospective of using impersonalised exosomes, and will greatly increase the feasibility of designing exosome-based vaccines or therapeutic approaches in humans.

IgG subclass profile among anti-Glutathione S-transferase T1 antibodies in post-transplant de novo immune hepatitis.

Although the pathogenic pathways leading to de novo immune hepatitis (IH) are not completely understood, we have shown strong evidences of an antidonor response against Glutathione S-transferase T1 (GSTT1), an antigen exclusively expressed in the donor liver. The first sign of this process is the production of GSTT1 antibodies that, in 25% of the cases, will precede de novo IH. Because the presence of the antibodies is not sufficient to trigger the disease, we aimed to study GSTT1 IgG subclasses in a group of 18 liver transplant patients, 12 that developed de novo IH and 6 that remained free of disease. Surprisingly, the predominant subclasses were IgG1-GSTT 1 and IgG4-GSTT 1. The presence of IgG4-expressing plasma cells was also investigated in 10 available liver biopsies. Six biopsies coinciding with diagnosis showed a mean value of 32.8 IgG4+ plasma cells/hpf vs. 5.55 in patients without the disease. We have not found a distinctive GSTT1-IgG profile in patients with de novo IH, but the ratio IgG1-GSTT 1 /IgG4-GSTT 1 in samples from close to the time of diagnosis seemed to be important. The novel finding of abundant IgG4-GSTT 1 in liver transplantation is intriguing, but their possible role in pathogenesis of de novo IH remains unknown.

Lethality of Opioid Overdose in a Community Cohort of Young Heroin Users.

BACKGROUND: The aim of the study was to estimate the lethality of opioid overdose among young heroin users. METHODS: A prospective community cohort study was conducted in Barcelona and Madrid, Spain. Participants included 791 heroin users aged 18-30 years who were followed up between 2001 and 2006. Fatal overdoses were identified by record linkage of the cohort with the general mortality register, while non-fatal overdoses were self-reported at baseline and follow-up interviews. The person-years (py) at risk were computed for each participant. Fatal and non-fatal overdose rates were estimated by city. Transition towards injection shortly before the overdose could not be measured. Overdose lethality (rate of fatal overdose in proportion to total overdose) and its 95% CI was estimated using Bayesian models. RESULTS: The adjusted rates of fatal and non-fatal opioid overdose were 0.7/100 py (95% CI: 0.4-1.1) and 15.8/100 py (95% CI: 14.3-17.6), respectively. The adjusted lethality was 4.2% (95% CI: 2.5-6.5). CONCLUSIONS: Four out of 100 opioid overdoses are fatal. These are preventable deaths that could be avoided before or after the overdose takes place. Resources are urgently needed to prevent fatal opioid overdose.