Olink Bioscience (Sweden)

BackgroundRecent proteomic analyses of biofluids have identified numerous emerging dementia biomarker candidates.MethodWe reviewed 39 dementia proximity extension assay (PEA) studies of cerebrospinal fluid (CSF) and blood (including UK Biobank data) published between 2021 and 2025 to identify trends in emerging dementia biomarkers.ResultsOur analysis revealed that the 39 dementia studies identified over 180 proteins regulated in human biofluids. Multiple studies confirmed the value of established biomarkers such as GFAP (astrocytic activation), NFL (neurodegeneration), and IL6 (inflammation). Twenty‐six proteins, including IL6, MMP10, GDF15, NEFL, CDCP1, ITGB2, CXCL9, IGFBP2, and GFAP, were identified in multiple studies, while 104 proteins were uniquely identified in a single study. Thirteen publications utilized UK Biobank data. We highlighted key pathways and trends in emerging dementia biofluid biomarkers based on PEA analysis. These studies focused on various biomarker types spanning at least four FDA biomarker classes: risk, diagnostic, prognostic, and pharmacodynamic.ConclusionRecent biofluid proteomic studies have identified novel risk, diagnostic, prognostic, and pharmacodynamic biomarker candidates for cognitive decline, warranting further validation.

Heart failure guidelines have recently introduced a narrow category with mildly reduced left ventricular ejection fraction (LVEF) (heart failure with mildly reduced ejection fraction; LVEF 41%-49%) between the previous categories of reduced (heart failure with reduced ejection fraction; LVEF ≤40%) and preserved (heart failure with preserved ejection fraction; LVEF ≥50%) ejection fraction. Grouping of continuous measurements into narrow categories can be questioned if their variability is high. We constructed a cohort of all 9716 new cases of chronic heart failure with an available LVEF in Stockholm, Sweden, from January 1, 2015, until December 31, 2020. All values of LVEF were collected over time, and patients were followed up until death, moving out of Stockholm, or end of study. Mixed models were used to quantify within-person variance in LVEF, and multistate Markov models, with death as an absorbing state, to quantify the stability of LVEF categories. LVEF values followed a normal distribution. The SD of the within-person variance in LVEF over time was 7.4%. The mean time spent in any LVEF category before transition to another category was on average <1 year for heart failure with mildly reduced ejection fraction. Probabilities of transitioning between categories during the first year were substantial; patients with heart failure with mildly reduced ejection fraction had a probability of <25% of remaining in that category 1 year later. LVEF follows a normal distribution and has considerable variability over time, which may impose a risk for underuse of efficient treatment. The heart failure with mildly reduced ejection fraction category is especially inconstant. Assumptions of a patient's current LVEF should take this variability and the normal distribution of LVEF into account.

Biomarkers for early detection of breast cancer may complement population screening approaches to enable earlier and more precise treatment. The blood proteome is an important source for biomarker discovery but so far, few proteins have been identified with breast cancer risk. Here, we measure 2929 unique proteins in plasma from 598 women selected from the Karolinska Mammography Project to explore the association between protein levels, clinical characteristics, and gene variants, and to identify proteins with a causal role in breast cancer. We present 812 cis-acting protein quantitative trait loci for 737 proteins which are used as instruments in Mendelian randomisation analyses of breast cancer risk. Of those, we present five proteins (CD160, DNPH1, LAYN, LRRC37A2 and TLR1) that show a potential causal role in breast cancer risk with confirmatory results in independent cohorts. Our study suggests that these proteins should be further explored as biomarkers and potential drug targets in breast cancer.

Cardiovascular inflammation and vascular endothelial dysfunction are involved in chronic heart failure (CHF), and cellular adhesion molecules are considered to play a key role in these mechanisms. We evaluated temporal patterns of 12 blood biomarkers of cell adhesion in patients with CHF. In 263 ambulant patients, serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (1.4–2.5) years. The primary endpoint (PE) was a composite of cardiovascular mortality, HF hospitalization, heart transplantation and implantation of a left ventricular assist device and was reached in 70 patients. We selected the baseline blood samples in all patients, the two samples closest to a PE, or, for event-free patients, the last sample available. In these 567 samples, associations between biomarkers and PE were investigated by joint modelling. The median age was 68 (59–76) years, with 72% men and 74% New York Heart Association class I–II. Repeatedly measured levels of Complement component C1q receptor (C1qR), Cadherin 5 (CDH5), Chitinase-3-like protein 1 (CHI3L1), Ephrin type-B receptor 4 (EPHB4), Intercellular adhesion molecule-2 (ICAM-2) and Junctional adhesion molecule A (JAM-A) were independently associated with the PE. Their rates of change also predicted clinical outcome. Level of CHI3L1 was numerically the strongest predictor with a hazard ratio (HR) (95% confidence interval) of 2.27 (1.66–3.16) per SD difference in level, followed by JAM-A (2.10, 1.42–3.23) and C1qR (1.90, 1.36–2.72), adjusted for clinical characteristics. In conclusion, temporal patterns of C1qR, CDH5, CHI3L1, EPHB4, ICAM2 and JAM-A are strongly and independently associated with clinical outcome in CHF patients.

To investigate whether we can identify different patterns of inflammation in the aqueous humor of a uveal melanoma (UM)-containing eye, and whether these are related to prognosis. Ninety samples of aqueous humor from UM-containing eyes were analyzed using a high-throughput multiplex immunoassay that enables simultaneous analysis of 92 predefined protein biomarkers. Cytokine expression was compared to clinical and histopathological characteristics. Cluster analysis was performed, after which the clusters were compared with clinical and histopathological tumor characteristics. Cluster analysis revealed three distinct clusters, with one cluster showing hardly any inflammatory cytokines, one showing intermediate levels, and one showing a high expression of inflammation-related biomarkers. Significant differences between the clusters were seen with regard to patient age (P = 0.008), tumor prominence (P = 0.001), ciliary body involvement (P < 0.001), American Joint Committee on Cancer (AJCC) stage (P < 0.001), monosomy of chromosome 3 (P = 0.03), and gain of chromosome 8q (P = 0.04), with the cluster with a highest cytokine expression having the worst prognostic markers. Especially apoptosis-related cytokines were differentially expressed. Analysis of cytokines in the aqueous humor shows distinct differences between aqueous humor samples and allocates these samples into three different prognostic tumor clusters. Especially large tumors with ciliary body involvement and monosomy 3 were associated with many cytokines, especially apoptosis-related cytokines. The presence of these cytokines in the aqueous humor may play a role in the lack of effective antitumor immune responses.

This article investigates whether longitudinally measured fibrinolysis factors are associated with cardiac events in patients with chronic heart failure (CHF). A median of 9 (interquartile range [IQR] 5-10) serial, tri-monthly blood samples per patient were prospectively collected in 263 CHF patients during a median follow-up of 2.2 (IQR 1.4-2.5) years. Seventy patients (cases) reached the composite endpoint of cardiac death, heart failure hospitalization, left ventricular assist device, or heart transplantation. From all longitudinal samples, we selected baseline samples in all patients and the last two samples before the event in cases or the last sample available in event-free patients. Herein, we measured plasminogen activator inhibitor 1 (PAI-1), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), and soluble urokinase plasminogen activator surface receptor (suPAR). Associations between temporal biomarker patterns during follow-up and the cardiac event were investigated using a joint model. Cases were on average older and showed higher New York Heart Association class than those who remained event-free. They also had lower blood pressures, and were more likely to have diabetes, renal failure, and atrial fibrillation. Longitudinally measured PAI-1, uPA, and suPAR were independently associated with adverse cardiac events after correction for clinical characteristics (hazard ratio [95% confidence interval]) per standard deviation increase of 2.09 (1.28-3.45) for PAI-1, 1.91 (1.18-3.24) for uPA, and 3.96 (2.48-6.63) for suPAR. Serial measurements of tPA were not significantly associated with the event after correction for multiple testing. Longitudinally measured PAI-1, uPA, and suPAR are strongly associated with adverse cardiac events during the course of CHF. If future research confirms our results, these fibrinolytic factors may carry potential for improved, and personalized, heart failure surveillance and treatment monitoring.

Background: Proximity extension assays (PEA) can compare concentrations of multiple proteins across biological samples and utilises the specificity of antibody proximity and the sensitivity of polymerase chain reaction to detect proteins of interests. As part of IBD Character, we performed high-throughput prospective case-control serum profiling to identify proteins that can predict Inflammatory Bowel Disease (IBD) and its disease course. Methods: Serum profiling was performed in treatment naïve newly diagnosed IBD and Non-IBD (symptomatic and healthy controls) using PEA panels (Olink Proteomics). Phenotypic data were obtained for all patients and follow up outcome data were captured for the Edinburgh and Oslo IBD cohorts. Treatment escalation was defined as the need for surgery and/or biologic therapies after initial induction of remission. Linear models were created for each protein including age and sex as covariates. Statistical analysis was performed using R. Results: Protein profiles were available in 635 patients (152 CD, 159 UC, 26 IBD-U, 298 non-IBD). 61 protein markers were significantly associated with IBD including MMP12 (Holm-adjusted p=4.1×10–26). Mapping the top markers to the cell-specific FANTOM 5 [1], several differentially expressed proteins originate from innate and adaptive immune cells such as dendritic cells. As diagnostic markers, 5 proteins differentiate UC from CD including MMP-12 (p= p=4.6×10–4) Follow up data were available for 206 patients. A total of 25 (32%), 21 (18%) and 2 (18%) patients required treatment escalation in the CD, UC and IBDU respectively. The data were randomly split into a testing (n=124) and a validation cohort (n=82). Using multivariable analyses with age, sex and follow up time as covariates, 9 proteins survived Holm adjustment and 8 of these proteins significantly predicted escalation in the validation cohort. 1000 iterations of unsupervised linear discriminant consensus clustering were performed using 7 randomly selected top protein probes. This identified 2 patients groups that had significantly different disease courses:logrank p=2.2×10–10, HR 5.6 (2.0–15.6), outperforming conventional biomarkers in predicting treatment escalation (hsCRP >4 mg/L, HR 3.2 (1.7–5.8), logrank p=0.0003 and Alb <36 g/L, HR 2.7 (1.4–5.2), p=0.0004). Figure 1 Conclusions: We have identified immune cell-specific PEA-based serum proteins that can diagnose IBD and predict disease course. These data demonstrate the translational potential of a PEA based technology in IBD

Amino acids are known to play a key role in gene expression regulation, and in mammalian cells, amino acid signaling is mainly mediated via two pathways, the mammalian target of rapamycin complex 1 (mTORC1) pathway and the amino acid responsive (AAR) pathway. It is vital for cells to have a system to sense amino acid levels, in order to control protein and amino acid synthesis and catabolism. Amino acid transporters are crucial in these pathways, due to both their sensing and transport functions. In this large‐scale study, an immortalized mouse hypothalamic cell line (N25/2) was used to study the gene expression changes following 1, 2, 3, 5 or 16 h of amino acid starvation. We focused on genes encoding solute carriers (SLCs) and putative SLCs, more specifically on amino acid transporters. The microarray contained 28 270 genes and 86.2% of the genes were expressed in the cell line. At 5 h of starvation, 1001 genes were upregulated and 848 genes were downregulated, and among these, 47 genes from the SLC superfamily or atypical SLCs were found. Of these, 15 were genes encoding amino acid transporters and 32 were genes encoding other SLCs or atypical SLCs. Increased expression was detected for genes encoding amino acid transporters from system A, ASC, L, N, T, xc‐, and y+. Using GO annotations, genes involved in amino acid transport and amino acid transmembrane transporter activity were found to be most upregulated at 3 h and 5 h of starvation.

Kutsal inanan bir insan icin yasam kaynagidir, sira disidir, olaganustudur, gizemlidir. Kutsala inanan kisi, kutsal addettigi degere her zaman saygi ve ilgi duymakta, kutsaldan bir medet ummaktadir. Oysa Tanri’nin disindaki kutsal olanlar, kutsalliklarini Tanri’ya olan nispetlerinden alirlar. Bu mânada Tanriya inanmayan insanlarin kutsala saygilari ve kutsallik inanclari yoktur. Islam'da ise kutsalin merkezi ve kaynagi Allah'tir. Peygamberler dahil olmak uzere Allah nezdinde makbul olan siddiklar, sehidler, sâlihler, ayrica insanlarin asiri sevgi besledigi veli ve ermisler, hatta meleklerden hicbirisi kutsiyetin mahiyetini olusturan “yaratilmislik ustu ve askin” ozelligi tasimaz. Bugun bazi Muslumanlarin bir takim kisi, turbe, degerleri asiri yuceltmelerinin nedeni, bilgi ve tevhid kaynagi olan Kuran'dan ve Hz. Muhammed'in ogretilerinden uzaklasmalarinda yatmaktadir. Bazi Muslumanlarin turbelere ve velilerin, ermislerin mezarlarina tapinma derecesine varabilen bagliliklari, ayni cahiliye donemi insanlarinin putlara ve kahinlere tapinmalarina benzemektedir. Sah damarindan daha yakin olan Allah'i terk edip turbelerde ve bazi mubarek ziyaret yerlerinde bir yardimda, istekte bulunmak, tevhid dini olan Islam itikadina aykiri davranistir. Allah kuluna tek basina kafi olup, O'nun yaninda yardimci kabul etmek, ona ulasmak icin bazi degerleri araci kilmak en buyuk gunah olan sirke dogru yol acabilmektedir.