Tissue factor binds to and inhibits interferon-α receptor 1 signaling.

Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in PodΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.

Tracking of serum lipids in healthy children on a year-to-year basis.

OBJECTIVES: To assess the stability of lipid profiles throughout childhood and evaluate their onset and dynamic. MATERIALS AND METHODS: Lipid markers were longitudinally measured in more than 1300 healthy children from the LIFE Child study (Germany) and categorized into normal, at-risk, or adverse. Year-to-year intra-person persistence of the categories during follow-ups was examined and Pearson's correlation coefficient was calculated. RESULTS: We found strong positive correlations for TC, LDL-C and ApoB (r > 0.75, p < 0.001) from the age of four years. Correlations were lowest during the first two years of life. Most children with normal levels also had normal levels the following year. Children with at-risk levels showed a tendency towards normal levels at the follow-up visit. Adverse levels of TC, LDL-C, ApoB (all ages), and HDL-C (from age 15) persisted in more than half of the affected children. Age-dependent patterns of stability were most pronounced and similar for TC, LDL-C, and ApoB. CONCLUSIONS: Normal levels of serum lipids show high stability and adverse levels stabilized in early childhood for TC, LDL, and ApoB. At-risk and adverse levels of TC, LDL-C or ApoB may warrant further or repeated diagnostic measurements with regards to preventing CVD in the long run.

Differences in white matter hyperintensities in socioeconomically deprived groups: results of the population-based LIFE Adult Study.

OBJECTIVE: Previous studies have shown that socioeconomically deprived groups exhibit higher lesion load of the white matter (WM) in aging. The aim of this study was to (i) investigate to what extent education and income may contribute to differences in white matter hyperintensities (WMHs) and (ii) identify risk profiles related to a higher prevalence of age-associated WMH. DESIGN AND SETTING: Population-based adult study of the Leipzig Research Centre for Civilization Diseases (LIFE) in Leipzig, Germany. PARTICIPANTS: Dementia-free sample aged 40-80 years (n = 1,185) derived from the population registry. MEASUREMENTS: Information was obtained in standardized interviews. WMH (including the derived Fazekas scores) were assessed using automated segmentation of high-resolution T1-weighted anatomical and fluid-attenuated inversion recovery (FLAIR) MRI acquired at 3T. RESULTS: Despite a significant association between income and WMH in univariate analyses, results from adjusted models (age, gender, arterial hypertension, heart disease, and APOE e4 allele) indicated no association between income and WMH. Education was associated with Fazekas scores, but not with WMH and not after Bonferroni correction. Prevalence of some health-related risk factors was significantly higher among low-income/education groups. After combining risk factors in a factor analysis, results from adjusted models indicated significant associations between higher distress and more WMH as well as between obesity and more deep WMH. CONCLUSIONS: Previously observed differences in WMH between socioeconomically deprived groups might stem from differences in health-related risk factors. These risk factors should be targeted in prevention programs tailored to socioeconomically deprived individuals.

Clonal Hematopoiesis Mutations Are Present in Atherosclerotic Lesions in Peripheral Artery Disease.

Clonal hematopoiesis (CH)-associated mutations increase the risk of atherosclerotic cardiovascular diseases. However, it is unclear whether the mutations detected in circulating blood cells can also be detected in tissues associated with atherosclerosis, where they could affect physiology locally. To address this, the presence of CH mutations in peripheral blood, atherosclerotic lesions and associated tissues was assessed in a pilot study of 31 consecutive patients with peripheral vascular disease (PAD) who underwent open surgical procedures. Next-generation sequencing was used to screen the most commonly mutated loci (DNMT3A, TET2, ASXL1 and JAK2). Twenty CH mutations were detected in peripheral blood of 14 (45%) patients, 5 of whom had more than one mutation. TET2 (11 mutations, 55%) and DNMT3A (8 mutations, 40%) were the most frequently affected genes. Altogether, 88% of the mutations detectable in peripheral blood were also present in the atherosclerotic lesions. Twelve patients also had mutations in perivascular fat or subcutaneous tissue. The presence of CH mutations in PAD-associated tissues as well as in blood suggests that CH mutations may make a previously unknown contribution to PAD disease biology.

Interplay between adipose tissue secreted proteins, eating behavior and obesity.

PURPOSE: Adipokines may play an important role in the complex etiology of human obesity and its metabolic complications. Here, we analyzed the relationship between 15 adipokines, eating behavior and body-mass index (BMI). METHODS: The study included 557 participants of the Sorbs (62.1% women, 37.9% men) and 3101 participants of the population-based LIFE-Adult cohorts (53.4% women, 46.4% men) who completed the German version of the Three-Factor-Eating Questionnaire to assess the eating behavior types cognitive restraint, disinhibition and hunger. Serum levels of 15 adipokines, including adiponectin, adipocyte fatty acid-binding protein (AFABP), angiopoietin-related growth factor (AGF), chemerin, fibroblast growth factor (FGF)-19, FGF-21, FGF-23, insulin-like growth factor (IGF)-1, interleukin (IL) 10, irisin, progranulin, vaspin, pro-neurotensin (pro-NT), pro-enkephalin (PENK) and leptin were measured. Based on significant correlations between several adipokines with different eating behavior items and BMI, we conducted mediation analyses, considering the eating behavior items as potential mediation variable towards BMI. RESULTS: Here, we found that the positive association between chemerin, AFABP or leptin and BMI in Sorbian women was mediated by higher restraint or disinhibited eating, respectively. Additionally, in Sorbian women, the negative relation between IGF-1 and BMI was mediated by higher disinhibition and the positive link between AGF and BMI by lower disinhibition. In Sorbian men, the negative relationship between PENK and BMI was mediated by lower disinhibition and hunger, whereas the negative relation between IGF-1 and BMI was mediated by higher hunger. In the LIFE-Adult women´s cohort, associations between chemerin and BMI were mediated by decreased hunger or disinhibition, respectively, whereas relations between PENK and BMI were fully mediated by decreased disinhibition. CONCLUSION: Our study suggests that adipokines such as PENK, IGF-1, chemerin, AGF, AFABP and leptin might affect the development of obesity by directly modifying individual eating behavior. Given the observational nature of the study, future experimental or mechanistic work is warranted.

Calcitonin measurement in pediatrics: reference ranges are gender-dependent, validation in medullary thyroid cancer and thyroid diseases.

BACKGROUND: There is only limited information on serum reference ranges of calcitonin (CT) in infants, children and adolescents. This gap hampers valid diagnostics in patients with multiple endocrine neoplasia type 2 (MEN 2) and planned prophylactic thyroidectomy. In addition, age-dependent reference ranges for CT are necessary to define a cure in medullary thyroid carcinoma (MTC). We asked whether the reference ranges for CT levels were age- and gender-dependent in the serum of a pediatric cohort. METHODS: A total of 6090 serum samples of 2639 subjects of the LIFE-Child cohort aged between 1 month and 17.9 years were analyzed by the CT electrochemiluminescence immunoassay (ECLIA). Reference intervals were estimated using the LMS method. For clinical validation the serum of 28 patients (61 samples) with MEN 2 and 106 patients (136 samples) with thyroid diseases were analyzed. RESULTS: CT levels showed a clear age- and gender-dependence with significantly higher values in boys (p<0.01). An accelerated decline of CT levels from newborn to children at the age of 4 and 5 years was observed for both sexes. A cure for MTC was demonstrated in 71% of MEN 2 patients after thyroidectomy, whereas 5 patients remained suspicious for micrometastasis or relapse. Only 1.5% of our patients with thyroid diseases revealed increased CT levels. CONCLUSIONS: This is the largest study to establish novel pediatric reference ranges from the CT values of healthy subjects. It allows a precise laboratory monitoring of CT in pediatric patients with MEN 2. Thyroid diseases did not have a relevant influence on CT levels in our pediatric cohort.

Stress-related hormones in association with periodontal condition in adolescents-results of the epidemiologic LIFE Child study.

OBJECTIVES: The aim of this study was to investigate the associations between blood levels of stress-related hormones and early signs of periodontal disease in children and adolescents. MATERIALS AND METHODS: Within the LIFE (Leipzig research center for civilization diseases) Child study, 498 adolescents (10 to 18 years) were included. Early signs of periodontal inflammation were measured by probing depth (PD) at six index teeth (16, 11, 26, 36, 31, 46). Blood levels of stress-related hormones (cortisol, dehydroepiandosterone-sulfate [DHEA-S]) and, additionally interleukine-6 (IL-6) were measured. Socioeconomic status, oral hygiene, orthodontic appliances, and nutritional status, recorded by body-mass-index-standard-deviation-score (BMI-SDS), were considered as confounding factors. Additionally, in 98 participants, an oral chairside active matrix metalloproteinase-8 (aMMP-8) test was performed. Statistical tests are the Mann-Whitney U tests, chi-squared tests and multivariate logistic regression model. RESULTS: IL-6, BMI-SDS as well as positive aMMP-8 test result were significantly associated with maximum PD > 3 mm (p < 0.05). However, no statistically significant associations between stress-related hormones (cortisol and DHEA-S) and presence of maximum PD > 3 mm were found (p > 0.05). Higher DHEA-S and BMI were associated with positive aMMP-8 result, even after adjusting for age and gender (p = 0.027, padj = 0.026). CONCLUSION: The results reveal no associations between PD and stress-related hormones cortisol and DHEA-S. aMMP-8 test result might be associated with DHEA-S level. Nutritional status seems to influence periodontal disease in adolescents. CLINICAL RELEVANCE: DHEA-S and BMI-SDS show associations with early signs of periodontal disease in adolescents aged 10 to 18 years. This association should be confirmed by the investigation of high-risk groups.

Will the Real Coeliac Disease Please Stand Up? Coeliac Disease Prevalence in the German LIFE Child Study.

OBJECTIVES: Assessing the seroprevalence and the prevalence of definite coeliac disease (CD) in the German LIFE Child Health study cohort including immunoglobulin A (IgA) antibodies against tissue transglutaminase (IgA-TTG) in addition to IgG antibodies against deamidated gliadin peptides (IgG-DGP) and human leukocyte antigen (HLA)-DQ2/8 genotyping. METHODS: Samples from children and adolescents were first screened for IgA-TTG and IgG-DGP. If IgA-TTG was above 0.5 times the upper limit of normal and/or IgG-DGP was positive, IgA antibodies against endomysium (IgA-EmA) were measured, and HLA was genotyped. In patients with only IgG-DGP positivity, total IgA was assayed. Subjects with suspicious results were followed up serologically and, in case of repeatedly positive antibody results, invited for a personal interview. Further diagnostic data were obtained independent from our study. RESULTS: We screened 2363 children's blood samples collected from 2011 to 2015. The seroprevalence, that is, IgA-TTG and/or IgA-EmA positivity or IgG-DGP positivity with IgA <0.05 g/L, was 1.57% (95% confidence interval [CI95%] 1.14-2.15). The prevalence of suspected CD, that is, seroprevalence and compatible HLA genotype with hitherto unknown mucosal damage, was 1.35% (CI95% 0.96-1.91). Definite CD, that is, seropositivity accompanied by positive intestinal biopsy or IgA-TTG ≥ 10 × upper limit of normal, was found in 0.42% (CI95% 0.22-0.80). Seven children claimed to have CD. The HLA haplotype, however, matched in only 4 of them resulting in an overall CD prevalence of at least 0.59% (CI95% 0.34-1.02). Thirteen unclear cases remained; therefore, the prevalence may even be higher. CONCLUSIONS: The prevalence of definite CD in a population-representative German cohort is higher than previously described. HLA-DQ typing is helpful to identify false-positive IgA-TTG patients negative for IgA-EmA and/or IgG-DGP under screening conditions and unmasks possible misdiagnoses of CD.

The LIFE Child study: a population-based perinatal and pediatric cohort in Germany.

The LIFE Child study is a large population-based longitudinal childhood cohort study conducted in the city of Leipzig, Germany. As a part of LIFE, a research project conducted at the Leipzig Research Center for Civilization Diseases, it aims to monitor healthy child development from birth to adulthood and to understand the development of lifestyle diseases such as obesity. The study consists of three interrelated cohorts; the birth cohort, the health cohort, and the obesity cohort. Depending on age and cohort, the comprehensive study program comprises different medical, psychological, and sociodemographic assessments as well as the collection of biological samples. Optimal data acquisition, process management, and data analysis are guaranteed by a professional team of physicians, certified study assistants, quality managers, scientists and statisticians. Due to the high popularity of the study, more than 3000 children have already participated until the end of 2015, and two-thirds of them participate continuously. The large quantity of acquired data allows LIFE Child to gain profound knowledge on the development of children growing up in the twenty-first century. This article reports the number of available and analyzable data and demonstrates the high relevance and potential of the study.

The LIFE-Adult-Study: objectives and design of a population-based cohort study with 10,000 deeply phenotyped adults in Germany.

BACKGROUND: The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies. METHODS/DESIGN: The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography. DISCUSSION: The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.

Plant sterols in food: no consensus in guidelines.

Plant sterols are supplemented in foods to reduce cardiovascular risk. Randomized controlled trials show 2 g of plant sterols a day reduce serum cholesterol by about 10%. This reduction in serum cholesterol levels is achieved at the expense of increased serum plant sterol levels. Findings in patients with phytosterolemia, in experimental studies and in clinical trials have lead to speculations that plant sterols might be atherogenic. In view of emerging safety issues the role of plant sterols in cardiovascular prevention has become controversial. This review reflects the ongoing controversial scientific debate and points out recent developments in guidelines of national and international societies.

Effect of biobanking conditions on short-term stability of biomarkers in human serum and plasma.

BACKGROUND: Liquid biobanking is an important tool for laboratory diagnostics in routine settings and clinical studies. However, the current knowledge about adequate storage conditions for different classes of biomarkers is incomplete and, in part, contradictory. Here, we performed a comprehensive study on the effects of different storage conditions on the stability of various biomarkers in human serum and plasma. METHODS: Serum and citrated plasma were aliquoted and stored at 4 °C, -20 °C, -80 °C, and <-130 °C for 0, 7, 30, and 90 days, respectively (5-10 pools/condition). Additionally, frozen aliquots were temporarily exposed to higher temperatures during storage to simulate removing individual samples. Stability was tested for 32 biomarkers from 10 different parameter classes (electrolytes, enzymes, metabolites, inert proteins, complement factors, ketone bodies, hormones, cytokines, coagulation factors, and sterols). RESULTS: Biobanking at -80 °C and <-130 °C for up to 90 days did not lead to substantial changes (defined as >3 interassay coefficients of variation and p<0.01) of any biomarker concentration. In contrast, storage at 4 °C and -20 °C induced substantial changes in single biomarker concentrations in most classes. Such substantial changes were increases (<20%) in electrolytes, metabolites, and proteins, and decreases (<96%) in enzymes, ketone bodies, cytokines, and coagulation factors. Biomarker stability was minimally affected by occasional short-term thermal exposure. CONCLUSIONS: Based on these results, we provide recommendations for storage conditions of up to 90 days for several biomarkers. Generally, storage at ≤-80 °C for at least 90 days including occasional short-term thermal exposure is an excellent storage condition for most biomarkers.

Bilirubin Levels in Infancy and Their Associations with Body Weight, Levels of Iron-Related Parameters and Steroid Hormone Levels.

It is assumed that bilirubin is hormonally regulated and influences weight development by preventing weight gain. However, studies in healthy infants are limited. The present study established reference values for bilirubin and investigated whether bilirubin levels are significantly associated with body weight, levels of ferritin and transferrin as well as steroid hormone levels in a study population of three- and six-month-old healthy infants. Data from a total of 411 study visits from the LIFE Child study (Leipzig, Germany) were analyzed. Associations were examined using linear regression analyses. Besides laboratory parameters, anthropometric data were gathered. We found statistically significant associations between body weight and bilirubin levels. In girls, we observed additional associations between bilirubin levels and both ferritin and transferrin concentrations at three months of age. At six months, steroid hormone levels were significantly associated with concentrations of total and indirect bilirubin, with effects differing by sex. Our study thus confirms associations already reported from animal studies and studies in adult populations. Furthermore, we showed that these associations already exist in the first year of life, are influenced by sex and age and, further, depend on the bilirubin type. Our results provide reference values for bilirubin and assist, therefore, in interpreting bilirubin levels in infancy.

Association of Whole Blood Amino Acid and Acylcarnitine Metabolome with Anthropometry and IGF-I Serum Levels in Healthy Children and Adolescents in Germany.

BACKGROUND: Physiological changes of blood amino acids and acylcarnitines during healthy child development are poorly studied. The LIFE (Leipziger Forschungszentrum für Zivilisationserkrankungen) Child study offers a platform with a large cohort of healthy children to investigate these dynamics. We aimed to assess the intra-person variability of 28 blood metabolites and their associations with anthropometric parameters related to growth and excess body fat. METHODS: Concentrations of 22 amino acids (AA), 5 acylcarnitines (AC) and free carnitine of 2213 children aged between 3 months and 19 years were analyzed using liquid chromatography/tandem mass spectrometry. Values were transformed into standard deviation scores (SDS) to account for sex- and age-related variations. The stability of metabolites was assessed through the coefficient of determination. Associations with parameters for body composition and insulin-like growth factor-I (IGF-I) SDS were determined by the Pearson correlation and linear regression. RESULTS: Our research revealed substantial within-person variation in metabolite concentrations during childhood and adolescence. Most metabolites showed a positive correlation with body composition parameters, with a notable influence of sex, pubertal status and weight group. Glycine exhibited negative associations with parameters of body fat distribution, especially in normal weight girls, overweight/obese boys and during puberty. CONCLUSION: Blood AA and AC measurements may contribute to elucidating pathogenesis pathways of adiposity-related comorbidities, but the specific timings and conditions of development during childhood and adolescence need to be taken into consideration.

Relationship of proteins and subclinical cardiovascular traits in the population-based LIFE-Adult study.

BACKGROUND AND AIMS: Understanding molecular processes of the early phase of atherosclerotic cardiovascular disease conditions is of utmost importance for early prediction and intervention measures. METHODS: We measured 92 cardiovascular-disease-related proteins (Olink, Cardiovascular III) in 2024 elderly participants of the population-based LIFE-Adult study. We analysed the impact of 27 covariables on these proteins including blood counts, cardiovascular risk factors and life-style-related parameters. We also analysed protein associations with 13 subclinical cardiovascular traits comprising carotid intima media thickness, plaque burden, three modes of Vicorder-based pulse-wave velocities, ankle-brachial index and ECLIA-based N-terminal prohormone of brain natriuretic peptide (NT-proBNP). RESULTS: Estimated glomerular filtration rate, triglycerides and sex where the most relevant covariables explaining more than 1 % variance of 49, 22 and 20 proteins, respectively. A total of 43 proteins were significantly associated with at least one of the analysed subclinical cardiovascular traits. NT-pro-BNP, brachial-ankle pulse-wave velocity (baPWV) and parameters of carotid plaque burden accounted for the largest number of associations. Association overlaps were relatively sparse. Only growth/differentiation factor 15, low density lipoprotein receptor and interleukin-1 receptor type 2 are associated with these three different cardiovascular traits. We confirmed several literature findings and found yet unreported associations for carotid plaque presence (von-Willebrand factor, galectin 4), carotid intima-media thickness (carboxypeptidase A1 andB1), baPWV (cathepsin D) and NT-proBNP (cathepsin Z, low density lipoprotein receptor, neurogenic locus homolog protein 3, trem-like transcript 2). Sex-interaction effects were observed, e.g. for spondin-1 and growth/differentiation factor 15 likely regulated by androgen response elements. CONCLUSIONS: We extend the catalogue of proteome biomarkers possibly involved in early stages of cardiovascular disease pathologies providing targets for early risk prediction or intervention strategies.

Relevance of GLP-1 receptor agonists or SGLT-2 inhibitors on the recruitment for clinical studies in patients with NAFLD.

INTRODUCTION: Guidelines increasingly recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) to prevent cardiovascular and cardiorenal endpoints. Both drugs also show beneficial effects in nonalcoholic fatty liver disease (NAFLD). Preexisting GLP-1 RA and SGLT2i therapies are frequently defined as exclusion criterion in clinical studies to avoid confounding effects. We therefore investigated how this might limit recruitment and design of NAFLD studies. METHODS: GLP-1 RA and SGLT2i prescriptions were analyzed in NAFLD patients with diabetes mellitus recruited at a tertiary referral center and from the population-based LIFE-Adult-Study. Individuals were stratified according to noninvasive parameters of liver fibrosis based on vibration-controlled transient elastography (VCTE). RESULTS: 97 individuals were recruited at tertiary care and 473 from the LIFE-Adult-Study. VCTE was available in 97/97 and 147/473 cases.GLP-1 RA or SGLT2i were used in 11.9% of the population-based cohort (LSM < 8 kPa), but in 32.0% with LSM ≥ 8 kPa. In the tertiary clinic, it was 30.9% overall, independent of LSM, and 36.8% in patients with medium and high risk for fibrotic NASH (FAST score > 0.35). At baseline, 3.1% of the patients in tertiary care were taking GLP-1 RA and 4.1% SGLT2i. Four years later, the numbers had increased to 15.5% and 21.6%. CONCLUSION: GLP-1 RA and SGLT2i are frequently and increasingly prescribed. In candidates for liver biopsy for NASH studies (VCTE ≥ 8 kPa) the use of them exceeds 30%, which needs careful consideration when designing NASH trials.

Update of the Minimum Information About BIobank Data Sharing (MIABIS) Core Terminology to the 3rd Version.

Introduction: The Minimum Information About BIobank Data Sharing (MIABIS) is a biobank-specific terminology enabling the sharing of biobank-related data for different purposes across a wide range of database implementations. After 4 years in use and with the first version of the individual-level MIABIS component Sample, Sample donor, and Event, it was necessary to revise the terminology, especially to include biobanks that work more in the data domain than with samples. Materials & Methods: Nine use-cases representing different types of biobanks, studies, and networks participated in the development work. They represent types of data, specific sample types, or levels of organization that were not included earlier in MIABIS. To support our revision of the Biobank entity, we conducted a survey of European biobanks to chart the services they provide. An important stakeholder group for biobanks include researchers as the main users of biobanks. To be able to render MIABIS more researcher-friendly, we collected different sample/data requests to analyze the terminology adjustment needs in detail. During the update process, the Core terminology was iteratively reviewed by a large group of experts until a consensus was reached. Results: With this update, MIABIS was adjusted to encompass data-driven biobanks and to include data collections, while also describing the services and capabilities biobanks offer to their users, besides the retrospective samples. The terminology was also extended to accommodate sample and data collections of nonhuman origin. Additionally, a set of organizational attributes was compiled to describe networks. Discussion: The usability of MIABIS Core v3 was increased by extending it to cover more topics of the biobanking domain. Additionally, the focus was on a more general terminology and harmonization of attributes with the individual-level entities Sample, Sample donor, and Event to keep the overall terminology minimal. With this work, the internal semantics of the MIABIS terminology was improved.

Mass Spectrometry Proteomics Characterization of Plasma Biomarkers for Colorectal Cancer Associated With Inflammation.

Background: Colorectal cancer (CRC) prognosis is determined by the disease stage with low survival rates for advanced stages. Current CRC screening programs are mainly using colonoscopy, limited by its invasiveness and high cost. Therefore, non-invasive, cost-effective, and accurate alternatives are urgently needed. Objective and design: This retrospective multi-center plasma proteomics study was performed to identify potential blood-based biomarkers in 36 CRC patients and 26 healthy volunteers by high-resolution mass spectrometry proteomics followed by the validation in an independent CRC cohort (60 CRC patients and 44 healthy subjects) of identified selected biomarkers. Results: Among the 322 identified plasma proteins, 37 were changed between CRC patients and healthy volunteers and were associated with the complement cascade, cholesterol metabolism, and SERPIN family members. Increased levels in CRC patients of the complement proteins C1QB, C4B, and C5 as well as pro-inflammatory proteins, lipopolysaccharide-binding protein (LBP) and serum amyloid A4, constitutive (SAA4) were revealed for first time. Importantly, increased level of C5 was verified in an independent validation CRC cohort. Increased C4B and C8A levels were correlated with cancer-associated inflammation and CRC progression, while cancer-associated inflammation was linked to the acute-phase reactant leucine-rich alpha-2-glycoprotein 1 (LRG1) and ceruloplasmin. Moreover, a 4-protein signature including C4B, C8A, apolipoprotein C2 (APO) C2, and immunoglobulin heavy constant gamma 2 was changed between early and late CRC stages. Conclusion: Our results suggest that C5 could be a potential biomarker for CRC diagnosis. Further validation studies will aid the application of these new potential biomarkers to improve CRC diagnosis and patient care.

Bispecific antibodies as bridging to BCMA CAR-T cell therapy for relapsed/refractory multiple myeloma.

Establishing a strategy for sequencing of T cell redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunological impact of bispecific T cell engaging antibodies (BsAb) as bridging therapy (BT) to subsequent BCMA-directed CAR-T cell therapies in 52 RRMM patients. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared to chemotherapy, anti-CD38 or anti-SLAMF7 antibody based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T cell expansion in patients receiving BsAb as BT. In vitro cytotoxicity of CAR-T cells was comparable amongst BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM.

Factor XII signaling via uPAR-integrin ß1 axis promotes tubular senescence in diabetic kidney disease.

Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12-/-) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin ß1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin ß1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin ß1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.