Background: The extracellular matrix (ECM) glycoprotein changes are associated with the pathogenesis and complications of atherosclerosis, leading to acute coronary syndrome (ACS). Tenascin-C (TNC), an ECM protein, has been implemented in the pathogenesis, diagnosis, and prognosis of patients with cardiovascular disease. Aim: The study aimed to compare the genetic variants of the TNC gene (rs13321, rs2104772, and rs12347433) between South Indians with ACS and healthy participants. Materials and Methods: This case-control study recruited 150 ACS patients as cases and 150 healthy participants as controls. TNC genotyping was performed using TaqMan 5\'-exonuclease allele discrimination assay. Serum TNC levels were measured by enzyme-linked immunosorbent assay. Results: Serum TNC levels were significantly higher in cases compared with controls. No significant difference was observed in allele and genotype frequencies of rs13321, rs2104772, and rs12347433 between cases and controls, which was confirmed by dominant, recessive, codominant, and homozygotic genetic models. The patients with heterozygous genotypes of rs13321, rs2104772, and rs12347433 had significantly lower serum TNC levels than patients with respective homozygous genotypes. Haplotype analyses revealed that the C-T-A haplotype in the block of rs13321-rs12347433-rs2104772 was associated with lower ACS risk (OR = 0.33, 95% CI: 0.15 - 0.75; p = 0.005). Also, the C-T-T and G-T-A haplotypes of the TNC gene were associated with higher and lower serum TNC levels, respectively. Conclusion: Our study demonstrated no genetic association between single nucleotide polymorphisms of the TNC gene and ACS risk; however, the C-T-A haplotype of the TNC gene might be associated with reduced ACS risk in South Indians.

Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European \"Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)\" study.
Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH.
DNA Methylation profiling classified 65.3% (n = 96/147) of cases as EPN-PFA and 15% (n = 22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99%-100% across 3 centers). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP-fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-center concordance and low sensitivity and specificity while MIP, MLPA, and DNA methylation-based approaches demonstrated greater accuracy.
We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q, and CDKN2A loss while FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches.

Lower back pain commonly arises from intervertebral disc (IVD) failure, often caused by deteriorating annulus fibrosus (AF) and/or nucleus pulposus (NP) tissue. High socioeconomic cost, quality of life issues, and unsatisfactory surgical options motivate the rapid development of non-invasive, regenerative repair strategies for lower back pain. This study aims to evaluate the AF regenerative capacity of injectable matrix repair strategy in ex vivo porcine organ culturing using collagen type-I and polycaprolactone nanofibers (PNCOL) with encapsulated fibroblast cells. Upon 14 days organ culturing, the porcine IVDs were assessed using gross optical imaging, magnetic resonance imaging (MRI), histological analysis, and Reverse Transcriptase quantitative PCR (RT-qPCR) to determine the regenerative capabilities of the PNCOL matrix at the AF injury. PNCOL-treated AF defects demonstrated a full recovery with increased gene expressions of AF extracellular matrix markers, including Collagen-I, Aggrecan, Scleraxis, and Tenascin, along with anti-inflammatory markers such as CD206 and IL10. The PNCOL treatment effectively regenerates the AF tissue at the injury site contributing to decreased herniation risk and improved surgical outcomes, thus providing effective non-invasive strategies for treating IVD injuries.

To which extent atrial remodeling occurs before atrial fibrillation (AF) is unknown.
The PREventive left atrial appenDage resection for the predICtion of fuTure Atrial Fibrillation (PREDICT-AF) study investigated such subclinical remodeling, which may be used for risk stratification and AF prevention.
Patients (N = 150) without a history of AF with a CHA2DS2-VASc score of ≥2 at an increased risk of developing AF were included. The left atrial appendage was excised and blood samples were collected during elective cardiothoracic surgery for biomarker discovery. Participants were followed for 2 years with Holter monitoring to determine any atrial tachyarrhythmia after a 50-day blanking period.
Eighteen patients (12%) developed incident AF, which was associated with increased tissue gene expression of collagen I (COL1A1), collagen III (COL3A1), and collagen VIII (COL8A2), tenascin-C (TNC), thrombospondin-2 (THBS2), and biglycan (BGN). Furthermore, the fibroblast activating endothelin-1 (EDN1) and sodium voltage-gated channel β subunit 2 (SCN2B) were associated with incident AF whereas the Kir2.1 channel (KCNJ2) tended to downregulate. The plasma levels of COL8A2 and TNC correlated with tissue expression and predicted incident AF. A gene panel including tissue KCNJ2, COL1A1, COL8A2, and EDN1 outperformed clinical prediction models in discriminating incident AF.
The PREDICT-AF study demonstrates that atrial remodeling occurs long before incident AF and implies future potential for early patient identification and therapies to prevent AF (ClinicalTrials.gov identifier NCT03130985).

The purpose of this study was to compare the immunohistochemical expression of tenascin-C (Tn-C) regarding clinicopathological variables and its association with the clinical behavior of central giant cell lesions (CGCLs). Forty-eight paraffin-embedded samples of CGCLs were selected. Based on clinical and radiographic features, the lesions were classified as aggressive (A-CGCLs) and non-aggressive (NA-CGCLs) subtypes. Histological assessment included the microvessel count (MVC), multinucleated giant cell (MGC) count, and the proportion of tissue area involved by mononuclear stromal cells/interstitial fibrosis. Immunoreactivity, immunolocalization, and distribution patterns of Tn-C were studied immunohistochemically. The association between Tn-C expression and clinicopathological characteristics was analyzed separately and adjusted for confounders using logistic regression models. A significantly greater proportion of cases with moderate-to-intense, intracellular, and diffuse staining of Tn-C was observed in A-CGCLs. CGCLs with a size ≥3.3 cm, fast growth, cortical disruption, high MVC/MGC counts, and low interstitial fibrosis showed a significantly greater frequency of moderate-to-intense, intracellular, and diffuse staining. Logistic regression analysis indicated a strong/independent association of these three immunohistochemical parameters with the aggressiveness of lesions. These data appear to suggest a possible role for Tn-C in the etiopathogenesis of CGCLs of the jaws, where its upregulation might favor the destructive behavior of A-CGCLs.

High blood pressure is the heritable risk factor for cardiovascular diseases. We investigated whether the presence of familial genetic and environmental risk factors are associated with increased risk of high blood pressure.
A total of 4,559 individuals from 401 families were included in this study. Familial aggregation analysis was carried out on systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI) and waist circumference (WC), and heritability was estimated for SBP and DBP. The association between familial risk factors and blood pressure traits including, incidence of hypertension, SBP and DBP was estimated separately using regression-based two-level Haseman-Elston (HE) method, with individual and familial BMI and WC as environmental exposures and familial genetic profile of known variants as genetic risk factors in 210 index families (≥2 hypertensive cases). Models were adjusted for the two nested sets of covariates.
During a follow-up of 15 years, the SBP, DBP, BMI and WC were highly correlated in inter class of mother-offspring and intraclass of sister-sister with heritability of 30 and 25% for DBP and SBP, respectively. Among index families, those whose members with higher familial BMI or WC had significantly increased risk of hypertension and consistent, strong signals of rs2493134 (AGT) linked with SBP and DBP, rs976683 (NLGN1) linked with SBP and HTN, and epistasis of rs2021783 (TNXB) and known genetic variants linked with all blood pressure traits.
Findings from this study show that familial genetic and environmental risk profile increase risk for high blood pressure beyond the effect of the individuals\' own risk factors.

To evaluate the genetic effects of sex hormone traits on the development of mental traits in middle-aged adults.
The SNPs associated with sex hormone traits were derived from a two-stage genome-wide association study (GWAS). Four sex hormone traits were selected in the current study, including sex hormone-binding globulin (SHBG), testosterone, bioavailable testosterone and estradiol. The polygenic risk score (PRS) of sex hormone traits were calculated from individual-level genotype data of the United Kingdom (UK) Biobank cohort. We then used logistic and linear regression models to assess the associations between individual PRS of sex hormone traits and the frequency of alcohol consumption, anxiety, intelligence and so on. Finally, gene-environment-wide interaction study (GEWIS) was performed to detect novel candidate genes interacting with the sex hormone traits on the development of fluid intelligence and the frequency of smoking and alcohol consumption by PLINK2.0.
We observed positive association between SHBG and the frequency of alcohol consumption (b = 0.0101, p = 3.84 × 10-11) in middle-aged males and females. In addition, estradiol was positively associated with the frequency of alcohol consumption (b = 0.0128, p = 1.96 × 10-8) in middle-aged males. Moreover, bioavailable testosterone was associated with the fluid intelligence (b = - 0.0136, p = 5.74 × 10-5) in middle-aged females. Finally, GEWIS identified one significant loci, Tenascin R (TNR) (rs34633780, p = 3.45 × 10-8) interacting with total testosterone for fluid intelligence.
Our study results support the genetic effects of sex hormone traits on the development of intelligence and the frequency of alcohol consumption in middle-aged adults in UK.

Pancreatic adenocarcinoma (PDAC) is the most frequent histological type of malignancy in the pancreas. Extracellular matrix (ECM), plays a critical role during the process of human carcinogenesis and the possible diversity in matricellular proteins composition of ECM may have a significant impact on the clinical course of PDAC. Aim of this paper was to evaluate the expression of three matricellular proteins, including Periostin (POSTN), Tenascin (TNS) and Osteopontin (OPN), in PDAC from long-survival (LS) and non-long survival (NLS) patients. A total of 30 PDAC were analyzed, 15 from patients that survived more than 60 months after surgery (LS) and 15 that died from the disease within 24 (NLS). RNA was extracted and OPN, TNS and POSTN mRNA levels were evaluated by qRT-PCR. LS and NLS samples showed the same type of POSTN and TN isoforms. On the contrary, OPN seems to be preferentially expressed in NLS PDAC. Moreover, OPNb and OPNc isoforms were expressed exclusively in NLS samples. In conclusion, Our data led to hypothesize a possible relationship between the expression of different isoforms of each of these proteins and the clinical outcome of patients with PDAC.

Tenascin C (TNC) is an extracellular matrix protein able to modulate the immune response. Knowledge regarding its role during sepsis and general critical illness is still limited. We here assessed the temporal dynamics of plasma TNC during sepsis and nonseptic critical illness, its capacity to predict patient outcome, and its specificity toward infection. TNC plasma concentrations were measured in 895 consecutive sepsis patients on ICU admission, day 2 and 4 thereafter, and, in a subset, before ICU discharge. To assess TNC diagnostic value, we compared patients with abdominal sepsis (N = 143) to noninfectious abdominal surgery controls (N = 98), and patients with severe community-acquired pneumonia (CAP, N = 227) to patients whose CAP diagnosis was retrospectively refuted (no-CAP controls, N = 70). Plasma TNC levels were persistently elevated in sepsis patients compared with healthy volunteers throughout the ICU stay. TNC levels varied by the site of infection and increased with the number of organs failing. Association of TNC levels with 30-day mortality could be wholly attributed to differences in disease severity. Noninfectious ICU patients also showed elevated TNC levels, albeit with different temporal dynamics. Although admission TNC was higher in CAP than in no-CAP patients, it performed poorly in distinguishing the 2 groups.TNC plasma levels are persistently elevated during sepsis and nonseptic critical illness. In sepsis patients, they are reflective of disease severity more than independent predictors of mortality. Despite higher levels in patients with infection compared with noninfectious controls, TNC does not perform sufficiently to be used as a standalone biomarker discriminating sepsis from noninfectious critical illness.

OBJECTIVE: Gastrointestinal symptoms are common in endometriosis, but the mechanisms behind these symptoms are yet poorly understood. Associations between endometriosis and irritable bowel syndrome (IBS), celiac disease, and various autoimmune diseases have been reported. These diseases express characteristic autoantibodies. The aim of the current study was to investigate autoantibodies against gonadotropin-releasing hormone 1 (GnRH1) and luteinizing hormone (LH) and their receptors, tenascin-C, matrix metalloproteinase-9, deamidated gliadin peptide, and tissue transglutaminase in a cohort of women with endometriosis, compared to controls and women with IBS or enteric dysmotility.
METHODS: One hundred seventy-two women with laparoscopy-verified endometriosis completed questionnaires regarding socio-demographics, lifestyle habits, medical history, and gastrointestinal symptoms, and sera were analyzed with ELISA for the abovementioned antibodies. Healthy female blood donors (N = 100) served as controls, and women with IBS or enteric dysmotility (N = 29) were used for comparison.
RESULTS: A non-significantly higher prevalence of IgM antibodies directed at tenascin-C (7.6% vs. 2.0%; p = 0.06) was the only observed difference in autoantibody levels in endometriosis compared to controls. Antibody presence was not associated with any clinical parameters. Patients with IBS or enteric dysmotility expressed higher levels of IgM antibodies against GnRH1 compared to both patients with endometriosis (p = 0.004) and healthy controls (p = 0.002), and higher levels of tenascin-C antibodies compared to healthy controls (17.2% vs. 2.0%; p = 0.006).
CONCLUSIONS: Women with endometriosis do not express higher prevalence of autoantibodies found to be characteristic in other patient groups with gastrointestinal symptoms.