Biomarker Patterns Research Articles

Soluble TAM receptor biomarkers: Neuroprotection in AD neuroinflammation?"

AbstractBackgroundWhile neuroinflammation is reckoned as a pathological hallmark of AD, research on suitable biomarkers is still ongoing. Here, we report on findings from the DZNE DELCODE, Fundacío ACE and other cohorts demonstrating distinct inflammatory biomarker profiles in CSF and serum. Intriguingly, within these profiles, soluble TAM receptor markers are elevated in neurodegeneration but still relate to protection of cognition and brain structure.MethodWe investigated a panel of 20 experimental biomarkers utilizing customized immunoassays in CSF and serum samples of DELCODE and other cohorts with a total of >1000 subjects, including healthy controls, subjective cognitive decline, mild cognitive impairment, AD relatives and AD patients. Data were analyzed in relation to clinical and biomarker‐based staging as well as cognitive and structural imaging composite scores, adjusted for covariates such as age.ResultVarious inflammatory markers, when measured in CSF, were found to correlate to tau isoforms and other neurodegeneration markers and to be elevated in pre‐dementia stage subjects with already pathological tau levels. Among these, soluble TAM receptors sAXL and sTyro3 were related to preserved cognition and brain structure. In serum, inflammatory markers displayed different interrelations, with individual proteins in serum showing no or modest correlation to their CSF counterparts or other AD biomarkers. Noteworthy, serum soluble AXL increased only in AD subjects and related to decreased structure and function.ConclusionNeurodegeneration in AD is accompanied by a pattern of elevated inflammatory CSF biomarkers. These proteins likely represent cellular responses to neuronal damage and are evident already at pre‐dementia stages of disease. Within this response, upregulation of TAM receptors in the brain could serve to regulate neuroinflammation and promote cellular survival, with receptor turnover resulting in elevated CSF levels. Noteworthy, blood signatures of the same biomarkers, though not without significance, show different patterns of relations towards disease features, likely reflecting distinct peripheral cellular origins and biological functions of the respective proteins. These findings point towards TAM signalling as potential target for future therapeutic intervention, especially in subjects with pre‐dementia neurodegeneration phenotypes. As such, CSF soluble TAM levels might provide promising readout biomarkers.

A Cross‐sectional HABS‐HD study of Plasma Biomarkers of Cognitive Decline across Diagnoses in a Diverse Community Cohort

AbstractBackgroundDue to their low cost, less invasive nature and ready availability, plasma biomarkers of Alzheimer’s disease have been proposed as one time screening tools for clinical trials and research. The impact of ethnoracial factors on these biomarkers has received little attention. The current study investigated the levels of Aβ40, Aβ42, total tau and NfL across diagnoses for each of the three major ethnoracial groups in the US in a community based cohort of older adults.Method1862 participants (852 Mexican Americans (MA); 775 Non‐Hispanic Whites (NHW) and 235 African Americans (AA)) drawn from The Health & Aging Brain Study – Health Disparities (HABS‐HD) study were included. Diagnoses were assigned using an algorithm (decision tree) verified by consensus review. Plasma samples were assayed using Simoa technology. Data were analyzed using ANOVA comparing the level of each biomarker across the cognitive diagnoses (Normal Cognition (NC), MCI & Dementia) within each ethnoracial group co‐varying age and sex.ResultFor NHW there were no significant differences between NC, MCI and Dementia groups in levels of Aβ40 or Aβ42. For t tau, MCI t tau was significantly higher than NC. The t tau level did not differ between the two cognitively impaired groups. There was a significant effect for diagnosis for NfL with the MCI NfL and the Dementia NfL level being significantly higher than the NC NfL level. The impaired groups did not differ in NfL between the impaired groups. For the MA significant differences across diagnoses were found only for NfL. The Dementia NfL level was significantly higher than the NC and significantly higher than the MCI. The only biomarker showing significant differences across diagnoses for AA was NfL. The Dementia NfL level was significantly higher than the NC and MCI levels.ConclusionAlthough cross‐sectional, the results suggest different patterns of plasma biomarkers across diagnoses for NHW as compared to MA and AA. NfL levels were highest in the Dementia group for all. Ongoing longitudinal research will show how biomarkers change as cognition declines.

The rationale behind the IWG criteria for Alzheimer's disease

AbstractBackgroundThe development of in‐vivo biomarkers has moved the diagnosis of Alzheimer’s disease from the dementia stage towards the prodromal stage, and has introduced the potential for preclinical diagnosis (ie, before symptom onset). These developments are relevant for the testing of potential therapies for secondary prevention of Alzheimer’s disease.MethodReview of the literatureResultIn 2018, the US National Institute on Aging and the Alzheimer’s Association proposed a purely biological definition of Alzheimer’s disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice, at least for the supposely preclinical stage of the disease. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. This was previously underlined by neuropathologists who indicate a consensus to disentangle the clinic‐pathological term ‘Alzheimer’s disease’ from the presence of Alzheimer lesions in the brain in their ‘NIA‐AA guidelines for the neuropathological assessment of Alzheimer’s disease’. Furthermore, a positive Alzheimer’s disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer’s disease pathology is present as a comorbidity.ConclusionIn line with these observations, the International Working Group recommend that Alzheimer’s disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer’s disease phenotypes, whereas biomarker‐positive cognitively unimpaired individuals should be considered only at‐risk for progression to Alzheimer’s disease.

Complement Biomarkers for Tracking Breakthrough Hemolysis in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients Treated with Last-Generation Complement Inhibitors

Background After the introduction of complement inhibitors targeting C5 (eculizumab, ravulizumab), the field of PNH has been revolutionized by the development of proximal complement inhibitors targeting C3 (pegcetacoplan), factor D (danicopan) or factor B (iptacopan). Since they are able to prevent C3-mediated extravascular hemolysis in addition to inhibit MAC-mediated intravascular hemolysis, these compounds result in better hematological responses, but breakthrough hemolysis (BTH) emerged as a possible adverse event. CH50, free-C5 and free-eculizumab have been used as assays useful to monitor therapeutic inhibition, but they remain specific for anti-C5 therapies only. Methods We investigated complement biomarkers searching for their association with clinically meaningful hemolysis. Instead of looking for residual complement activity, we tracked in vivo complement activation through the complement breakdown fragments sC5b-9, Bb, C4d (assessing terminal, alternative and classical pathways, respectively), and erythrocyte-bound C3d. We analyzed serial samples collected from 2 untreated patients who then received danicopan in monotherapy (total samples 83), and from 8 patients initially treated with eculizumab (total samples n=19), who then received iptacopan (total samples 263, combination therapy with eculizumab n=236, and monotherapy n=27). Data were correlated with clinical and laboratory hemolysis (lactate dehydrogenase, LDH). Results Samples collected from untreated patients highlight massive and broad complement activation, with increased sC5b-9 (2478±2151 ng/mL; n.r. 20-172), increased Bb (4.578±0.494 µg/mL; n.r. 0.060-0.566), but normal C4d (0.036±0.023 µg/mL; n.r. 0.033-0.219), demonstrating that it is the alternative pathway which enables the terminal pathway eventually causing hemolysis in PNH. Patients on the terminal inhibitor eculizumab treatment showed elevated Bb (3.378±2.124 µg/mL), and elevated sC5b-9 (1273±1007 ng/mL), even if this latter seems slightly lower as compared to that of untreated patients. Erythrocyte-bound C3d was detectable in all samples (32.3±19.2% C3d+ erythrocytes, n=56; n.r. <0.1), consistent with the notion that uncontrolled proximal complement enables C3-mediated extravascular hemolysis. Linear correlation between sC5b-9 or Bb and LDH was not observed, even if spikes of sC5b-9 were observed in concomitance with BTH (as demonstrated by rise of LDH). In contrast, the pattern of these complement biomarkers was quite different in patients receiving proximal complement inhibitors, consistent with their capability of intercepting upstream complement activation. On danicopan monotherapy, both Bb (1.874±0.739 µg/mL) and sC5b-9 (695±225 ng/mL) were lower as compared with pre-treatment values, and C3d deposition on erythrocytes was not detectable. Similarly, on iptacopan monotherapy, both Bb (1.815±1.215 µg/mL) and sC5b-9 (557±475 ng/mL) were lower as compared to baseline values, and C3d deposition on erythrocytes became undetectable. When Bb and sC5b-9 were correlated with LDH looking to all aggregate data, we could not find any linear correlation; thus, when tracked in condition of complete complement inhibition, these biomarkers could not predict BTH. Nevertheless, fluctuations and spikes of Bb or sC5b-9 were seen, and even if they were always associated with LDH increase, symptomatic clinical BTH was observed just occasionally, demonstrating that these biomarkers are useful to track subtle, transient leakages of complement inhibition. Conclusions Systematic investigation of biomarkers of complement terminal, alternative and classical pathways in PNH patients proves that proximal complement inhibitors disable also the terminal complement, eventually leading to prevention of both intravascular and extravascular hemolysis. Since Bb and sC5b-9 are significantly reduced most of the time, they fail in tracking clinically meaningful chronic residual intravascular hemolysis. Nevertheless, Bb and sC5b-9 are elevated in case of in case of acute hemolysis, confirming transient loss of therapeutic inhibition at time of BTH. Since subtle fluctuations of Bb and sC5b-9 can be seen also in absence of clinically meaningful hemolysis, they track low-level residual in vivo complement activation, which may help in understanding the pharmacodynamics of novel complement inhibitors and how to best use them.

Frailty is characterized by biomarker patterns reflecting inflammation or muscle catabolism in multi-morbid patients.

Frailty development is partly dependent on multiple factors like low levels of nutrients and high levels of oxidative stress (OS) and inflammation potentially leading to a muscle-catabolic state. Measures of specific biomarker patterns including nutrients, OS and inflammatory biomarkers as well as muscle related biomarkers like 3-methylhistidine (3MH) may improve evaluation of mechanisms and the complex networks leading to frailty. In 220 multi-morbid patients (≥ 60years), classified as non-frail (n=104) and frail (n=116) according to Fried's frailty criteria, we measured serum concentrations of fat-soluble micronutrients, amino acids (AA), OS, interleukins (IL) 6 and 10, 3MH (biomarker for muscle protein turnover) and serum spectra of fatty acids (FA). We evaluated biomarker patterns by principal component analysis (PCA) and their cross-sectional associations with frailty by multivariate logistic regression analysis. Two biomarker patterns [principal components (PC)] were identified by PCA. PC1 was characterized by high positive factor loadings (FL) of carotenoids, anti-inflammatory FA and vitamin D3 together with high negative FL of pro-inflammatory FA, IL6 and IL6/IL10, reflecting an inflammation-related pattern. PC2 was characterized by high positive FL of AA together with high negative FL of 3MH-based biomarkers, reflecting a muscle-related pattern. Frail patients had significantly lower factor scores than non-frail patients for both PC1 [median: -0.27 (interquartile range: 1.15) vs. 0.27 (1.23); P=0.001] and PC2 [median: -0.15 (interquartile range: 1.13) vs. 0.21 (1.38); P=0.002]. Patients with higher PC1 or PC2 factor scores were less likely to be frail [odds ratio (OR): 0.62, 95% CI: 0.46-0.83, P=0.001 for PC1; OR: 0.64, 95% CI: 0.48-0.86, P=0.003 for PC2] compared with patients with lower PC1 or PC2 factor scores. This indicates that increasing levels of anti-inflammatory biomarkers and increasing levels of muscle-anabolic biomarkers are associated with a reduced likelihood (38% and 36%, respectively) for frailty. Significant associations remained after adjusting the regression models for potential confounders. We conclude that two specific patterns reflecting either inflammation-related or muscle-related biomarkers are both significantly associated with frailty among multi-morbid patients and that these specific biomarker patterns are more informative than single biomarker analyses considering frailty identification.

Cardiac-specific deficiency of 3-hydroxy-3-methylglutaryl coenzyme A lyase in mice causes cardiomyopathy and a distinct pattern of acyl-coenzyme A-related biomarkers.

Deficiency of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase (HL) is an autosomal recessive inborn error of acyl-CoA metabolism affecting the last step of leucine degradation. Patients with HL deficiency (HLD) can develop a potentially fatal cardiomyopathy. We created mice with cardiomyocyte-specific HLD (HLHKO mice), inducing Cre recombinase-mediated deletion of exon 2 at two months of age. HLHKO mice survive, but develop left ventricular hypertrophy by 9 months. Also, within minutes after intraperitoneal injection of the leucine metabolite 2-ketoisocaproate (KIC), they show transient left ventricular hypocontractility and dilation. Leucine-related acyl-CoAs were elevated in HLHKO heart (e.g., HMG-CoA, 34.0 ± 4.4 nmol/g versus 0.211 ± 0.041 in controls, p &lt; 0.001; 3-methylcrotonyl-CoA, 5.84 ± 0.69 nmol/g versus 0.282 ± 0.043, p &lt; 0.001; isovaleryl-CoA, 1.86 ± 0.30 nmol/g versus 0.024 ± 0.014, p &lt; 0.01), a similar pattern to that in liver of mice with hepatic HL deficiency. After KIC loading, HMG-CoA levels in HLHKO heart were higher than under basal conditions, as were the ratios of HMG-CoA/acetyl-CoA and of HMG-CoA/succinyl-CoA. In contrast to the high levels of multiple leucine-related acyl-CoAs, biomarkers in urine and plasma of HLHKO mice show isolated hyper-3-methylglutaconic aciduria (700.8 ± 48.4 mmol/mol creatinine versus 37.6 ± 2.4 in controls, p &lt; 0.001), and elevated C5-hydroxyacylcarnitine in plasma (0.248 ± 0.014 μmol/L versus 0.048 ± 0.005 in controls, p &lt; 0.001). Mice with liver-specific HLD were compared, and showed normal echocardiographic findings and normal acyl-CoA profiles in heart. This study of nonhepatic tissue-specific HLD outside of liver reveals organ-specific origins of diagnostic biomarkers for HLD in blood and urine and shows that mouse cardiac HL is essential for myocardial function in a cell-autonomous, organ-autonomous fashion.

245 (PB-069) Poster - Exploring the lymph node’s microenvironment for personalized management of luminal A breast cancer

Background: Lymph nodes (LNs) are the main doorway for tumor cell metastasis from the primary site and its evaluation is a major prognostic factor. The One Step Nucleic Acid Amplification (OSNA) is being adopted worldwide for sentinel-LNs (SLNs) staging in breast cancer (BC). SLNs’ OSNA lysate may be used for gene expression studies, being the potentially ideal samples to search for new markers related to immune response. Using a targeted gene expression approach, we aim to identify transcriptomic patterns of SLNs immune response and biomarkers that may improve risk stratification and personalized therapy for patients with Luminal A early stage BC.

Formation of authigenic carbonates contributed by sulfate- and metal-driven anaerobic oxidation of methane in the northern Okinawa Trough, East China Sea

Authigenic carbonates of the northern Okinawa Trough have been shown to be contributed by both sulfate- and Fe-driven anaerobic oxidation of methane (SD-AOM and Fe-AOM, respectively); however, the microorganisms involved remain poorly constrained. To better understand the types and roles of microorganisms in specific biological methane oxidation processes, authigenic carbonates collected from the northern Okinawa Trough at water depths between ∼540 m and 700 m were studied using petrographic, mineralogical, elemental, and lipid biomarker analyses. The carbonate minerals were primarily aragonite, high-magnesium calcite, low-magnesium calcite, or dolomite. The extremely low δ13C values of bulk carbonates (−59.2‰), molecular fossils of anaerobic methane oxidizing archaea (ANME; −131‰), and sulfate-reducing bacteria (SRB; −77‰) indicated that the authigenic carbonates formed as products of AOM. Biogenic methane was confirmed to be the main carbon source for all carbonates, whereas bio-degraded oil and hydrothermal input complemented carbon sources, as revealed by the occurrence of unresolved complex mixture, strongly enriched As and Sb, and their correlations with Fe/Al. Combined with enriched δ18O values (as high as +5‰), the methane fluids were suggested to derive from the dissociation of gas hydrates. ANME-2 and a mixture of ANME-1 and ANME-2 were identified for the two calcitic carbonates, respectively, as revealed by their specific biomarker patterns. The relatively higher contents of 13C-depeleted isoprenoids and SRB−related fatty acids, strong Mo enrichment, and biological debris in both calcite- and aragonite-dominated carbonates reflect precipitation driven by SD-AOM in a shallow sulfate-methane transition. For other seep carbonates, low amounts of 13C-depeleted isoprenoids and the near absence of crocetane suggest dominance of the ANME-1 assemblage. The extremely low amounts and non-13C-depleted iso-/anteiso-C15:0 fatty acids (−27‰) in the dolomite-containing carbonates indicate the decoupling of ANME and SRB. These carbonates were most likely formed below or at the bottom of the sulfate-methane transition and included contributions from Fe-AOM, as indicated by the low Mo content, occurrence of dolomite and siderite, and decreased δ56Fe values with increasing Fe/Al ratios.

Photometric method for dual targeting of surface and surface-associated proteins on extracellular vesicles in the multiparametric test.

Extracellular vesicles (EVs) have become a topic of interest within the field of diagnostic biomarkers; however, recent developments in the study of EVs have increased the need for simpler but still comprehensive methods for characterization. Here, we describe how to simultaneously measure several surface or surface-associated proteins on EVs using a multiparametric microarray-based analysis termed Extracellular Vesicle Array (EV Array), which is developed to catch and phenotypically characterize small EVs. Previously, this analysis has been limited to measuring only one fluorescent signal per analysis. The analysis relies on antibodies printed onto a solid surface, for catching the EVs carrying the specific surface or surface-associated proteins, and on the subsequent fluorescent detection. For the optimization of detection, two antibodies with attached Cy3 or Cy5 were added to various combinations of the EV surface or surface-associated proteins: CD9, CD63, CD81, flotillin-1, and HSP90. In this study, the EV surface or surface-associated proteins were analyzed in human plasma from six healthy subjects. Changes observed in signal intensities from Cy3 and Cy5 related specifically to these combinations and allowed for a comparison of the two different fluorescent signals. When comparing the results, it was observed that it is possible to measure the EV surface or surface-associated proteins at both 532nm (Cy3) and 635nm (Cy5) simultaneously without a significant change in signals from the detection molecules. This allows us to measure multiple EV marker proteins in a single analysis, thereby more quickly finding complex biomarker patterns in a sample.

A re-appraisal of thrombogenesis in COVID-19, seen as a multiple Complex System

The aim of this essay is to re-consider the peculiar type of thrombogenesis observed in severe cases of COVID-19 infection, focusing on the multiple interconnected networks involved, such as inflammation, blood coagulation, fibrinolysis, and immune responses. These linked mechanisms can be assimilated to the “Complex Systems” (CS), that play a capital role in various domains: from physics to chemistry, biology and medicine, to social and behavioral sciences. CS are characterized by eliciting variable responses: their final results can be contradictory and often unpredictable. In fact, in severe COVID-19 various outcomes can occur, such as macro- and micro-thrombosis, vasculitis, hemorrhage, hyper and hypo fibrinolysis, distorted inflammatory and immune response, and others. The insight supplied by the CS theory in understanding thrombogenesis in COVID-19 can be useful in several ways. It recalls the importance of a “holistic” view of multiple patterns of signs, symptoms and biomarkers; stresses the added value of global versus mechanistic tests, particularly in coagulation and fibrinolysis; suggests building up small trials of selected patients in a perspective of precision medicine; discourages passive transfer of therapeutic choices from no- COVID to COVID patients; and finally indicates that some treatments, as the anti-inflammatory and the anti-coagulant ones, should be initiated as early as possible, so to avoid worsening of the condition by repetitive feedback and shortcut mechanisms.

Identification of Differentially Expressed microRNAs Associated with Ischemic Stroke by Integrated Bioinformatics Approaches.

Ischemic stroke (IS) is one of the leading causes of disability and mortality worldwide. This study aims to find the crucial exosomal miRNAs associated with IS by using bioinformatics methods, reveal potential biomarkers for IS, and investigate the association between the identified biomarker and immune cell pattern in the peripheral blood of IS patients. In this study, 3 up-regulated miRNAs (hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p) miRNAs in the serum exosomes between IS patients and healthy controls from GEO database (GSE199942) and 25 down-regulated genes of peripheral blood mononuclear cells of IS patients from GSE22255 were obtained with the help of the R software. GO annotation and KEGG pathway enrichment analysis showed that the 25 down-regulated genes were associated with coenzyme metabolic process and were mainly enriched in the N-glycan biosynthesis pathway. Furthermore, we performed the LASSO algorithm to narrow down the above 25 intersected genes, and identified 8 key genes which had a good diagnostic value in discriminating IS patients from the healthy controls analyzed with ROC curve. CIBERSORT algorithm indicated that the abundance of M0 macrophages and resting mast cells was significantly lower than that of the control group. The spearman correlation analysis showed that STT3A was negatively correlated with the proportion of follicular helper T cells, activated NK cells and resting dendritic cells. Finally, GSE117064 showed that has-miR-16-5p was more advantageous for diagnosing stroke. In conclusion, hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p are identified as specific related exosomal miRNAs for IS patients. These genes may provide new targets for the early identification of IS.

Biomarkers associated with coronary high-risk plaques

Vascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary high-risk plaques defined according to intravascular imaging have not been systematically studied. A total of 69 patients with coronary artery disease who underwent both optical coherence tomography and intravascular ultrasound imaging, and who provided blood specimens were included. Comprehensive biomarkers for inflammation, lipid, and coagulation were analyzed. Composite models sought biomarker patterns associated with thin-cap fibroatheroma (TCFA) and "high-risk plaques" (TCFA and large plaque burden). Two different composite models were developed for TCFA, based on the finding that high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1, fibrinogen, IL-6, homocysteine and amyloid A levels were elevated, and high-density lipoprotein cholesterol (HDL) and bile acid levels were decreased in these patients. Both composite models were highly accurate for detecting patients with TCFA (area under curve [AUC]: 0.883 in model-A and 0.875 in model-B, both p < 0.001). In addition, creatinine, hsCRP, fibrinogen, tumor necrosis factor-α, IL-6, homocysteine, amyloid A, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques". Two composite models were highly accurate for detection of patients with "high-risk plaques" (AUC: 0.925 in model-A and 0.947 in model-B, both p < 0.001). Biomarkers useful for detection of patients with high-risk coronary plaques defined according to intravascular imaging have been identified. These biomarkers may be useful to risk stratify patients and to develop targeted therapy.Clinical Trial Registration https://www.umin.ac.jp/ctr/ , UMIN000041692. Biomarkers and high-risk plaques hsCRP, PAI-1, fibrinogen, IL-6, homocysteine, amyloid A, HDL, and bile acid were useful for detecting patients with TCFA. hsCRP, fibrinogen, IL-6, homocysteine, amyloid A, creatinine, TNFα, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques" (plaque which has both TCFA and large plaque burden). White arrowhead denotes TCFA. Red and green dashed lines denote lumen area and external elastic membrane area, respectively.

Biomarkers associated with vulnerable plaques

Abstract Background Cardiovascular heart disease is the leading cause of mortality worldwide, with the rupture or thrombosis of an atherosclerotic plaque being the main reason behind an acute coronary syndrome. It has already been established that the morphology of atherosclerotic plaques determine their stability. A lipid rich lesion with a thin fibrous cap is more prone to rupture compared to solid fibrous lesions. In the PROSPECTII study we used Near infrared spectroscopy (NIRS) and Intravascular ultrasound (IVUS) to identify atherosclerotic plaques in the coronary arteries; NIRS-derived lipid core burden index (LCBI) and IVUS-derived plaque burden (PB) identified plaques that caused adverse cardiovascular events. Purpose Our aim is to find biomarkers associated with LCBI or PB, to understand the development of vulnerable plaques. Methods 902 patients were enrolled in this study after successful percutaneous coronary intervention (PCI). A combined NIRS-IVUS catheter was then used to analyze approximately 200m of coronary arteries. Blood samples for biomarker analysis were taken before the PCI procedure and plasma levels of 182 proteins associated with cardiovascular disease were assessed using a novel method for measuring proximity extension assay. Adjusted linear regression models were calculated between the biomarkers and the outcomes of interest, followed by a false discovery rate (FDR) correction. Results We found 24 proteins associated with plaque burden and 28 proteins associated with LCBI after using a cut off of two tailed P value &amp;lt;0.05. An overlap of 8 biomarkers could be seen between the two groups. After adjusting the P values with FDR, Angiopoeitin like 3 (ANGPTL3) retained its association to LCBI, and Interleukin 18 receptor 1 (IL18R1) and colony stimulating factor 1 (CSF-1) to plaque burden. Conclusion We were able to identify different biomarker patterns associated with plaque burden compared to lipid rich vulnerable plaques. ANGPTL3 was shown to only have an association with lipid rich plaques and not with solid fibrous lesions which further supports its role in vulnerable plaques. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Abbott Vascular, Infraredx, and The Medicines Company

Necrotizing Enterocolitis in Very Low Birth Weight Neonates: A Natural History Study.

We characterize the most recent natural history of necrotizing enterocolitis (NEC), as this is an essential first step in guiding the prevention and treatment of this disease in the present day. We performed a retrospective cohort study of neonates who were born at 23 to 29 weeks' gestation and birth weight <1,500 g who received care from the Pediatrix Medical Group between 2004 and 2019. We assessed the incidence of medical and surgical NEC and the patterns of initial antibiotic treatment to develop a contemporary cohort for further analysis. Among patients discharged between 2015 and 2019, we characterized the stage-specific risk factors for patients diagnosed with medical or surgical NEC, as well as patterns of disease onset, progression, biomarkers, and outcomes. We used the same approach to characterize patients diagnosed with suspected NEC. Among 34,032 patients in the contemporary cohort, 1,150 (3.4%) were diagnosed with medical NEC and 543 (1.6%) were diagnosed with surgical NEC. The temporal pattern of disease onset was different for medical and surgical NEC, with gestational age- and birth weight-specific risk disparities emerging earlier in surgical NEC. Thirty-day mortality was much greater among surgical NEC patients (medical NEC 16.4% vs. surgical NEC 43.0%), as were rates of various in-hospital and long-term outcomes. Suspected NEC was diagnosed in 1,256 (3.7%) patients, among whom risk factors and disease onset, progression, and outcomes closely resembled those of medical NEC. Analyzing data from a contemporary cohort enabled us to characterize the current, stage-specific natural history of NEC, including novel insights into suspected NEC. Future studies could leverage this cohort to characterize how specific patient characteristics, care processes, or biomarkers may influence or predict disease outcomes. · The incidence of NEC has reached a stable baseline in recent years.. · Risk factors for NEC vary in a stage-specific manner.. · The stage-specific onset and progression of NEC differ by gestational age and birth weight..

Transdiagnostic connectome signatures from resting-state fMRI predict individual-level intellectual capacity

Medication and other therapies for psychiatric disorders show unsatisfying efficacy, in part due to the significant clinical/ biological heterogeneity within each disorder and our over-reliance on categorical clinical diagnoses. Alternatively, dimensional transdiagnostic studies have provided a promising pathway toward realizing personalized medicine and improved treatment outcomes. One factor that may influence response to psychiatric treatments is cognitive function, which is reflected in one’s intellectual capacity. Intellectual capacity is also reflected in the organization and structure of intrinsic brain networks. Using a large transdiagnostic cohort (n = 1721), we sought to discover neuroimaging biomarkers by developing a resting-state functional connectome-based prediction model for a key intellectual capacity measure, Full-Scale Intelligence Quotient (FSIQ), across the diagnostic spectrum. Our cross-validated model yielded an excellent prediction accuracy (r = 0.5573, p < 0.001). The robustness and generalizability of our model was further validated on three independent cohorts (n = 2641). We identified key transdiagnostic connectome signatures underlying FSIQ capacity involving the dorsal-attention, frontoparietal and default-mode networks. Meanwhile, diagnosis groups showed disorder-specific biomarker patterns. Our findings advance the neurobiological understanding of cognitive functioning across traditional diagnostic categories and provide a new avenue for neuropathological classification of psychiatric disorders.

Comparison of biomarker expression in oral lichen planus and oral lichenoid lesions.

Oral lichen planus (OLP) and oral lichenoid lesions (OLL) comprise a group of oral mucosal disorders that have similar clinical and histological features. To compare the levels of investigated biomarkers in biopsied OLP and OLL, and to determine the pattern of biomarkers, which could be useful for the biological characterization of these 2 disorders. A total of 56 biopsy specimens in 2 groups were analyzed in this study. One group consisted of 25 idiopathic OLP lesions, and the other included 31 OLL from patients treated with antihypertensive and cardiac medications. The expression of protein p53, topoisomerase I (topo I), heat shock protein 90 (HSP90), and E-cadherin was analyzed using immunohistochemistry. The p53 protein expression showed a trend to a positive correlation with topo I expression in the total sample (p = 0.067, R = 0.25). The p53 protein and HSP90 expression was higher in the OLL group compared to the OLP group, but the difference was not statistically significant. No association was found between topo I and E-cadherin expression for either the OLP or OLL group. The findings of this study suggest that the slightly higher protein p53 and HSP90 expression in the OLL group might be caused by the medications used. The slight association between p53 and topo I expression indicates that the cooperation between these proteins might be essential for the growth of OLP/OLL in general. We conclude that the overexpression of p53 protein and high expression of topo I found in both types of lesions might induce their biologically aggressive behavior.

Identifying a novel serum microRNA biomarker panel for the diagnosis of childhood asthma.

The pathological mechanism of childhood asthma is complex, and timely diagnosis is the key to effective prevention and control of childhood asthma. We collected 170 serum samples from 95 children with asthma and 75 healthy children. Serum miRNA biomarkers were analyzed by Illumina sequencing for childhood asthma. Differentially serum miRNAs were confirmed with quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. The Illumina sequencing data showed the differential expression of 111 serum miRNAs among asthmatic and healthy children. After confirmation of miRNAs expression through qRT-PCR, four of them (namely hsa-miR-106a-5p, hsa-miR-18a-5p, hsa-miR-144-3p, and hsa-miR-375) manifested significant differential expression between asthmatic children and healthy controls. The biomarkers classification tree model created with these four miRNAs using the Biomarker Patterns Software could effectively separate childhood asthma and healthy children, with a specificity of 88.3%, a sensitivity of 95.0%, and an area under the curve (AUC) value of 0.942. The regulatory networks containing miRNAs and their gene targets suggested that the four miRNAs might have gene targets implicated in inflammation, immunity, and transcriptional efficiency. Taken together, this four-serum-miRNA panel is a promising biomarker to diagnose childhood asthma noninvasively.

Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib

While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor–positive/human epidermal growth factor receptor 2‒negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [≥second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs. Pfizer (NCT01740427; NCT01942135).

Risk of Type 2 Diabetes Among Individuals with Excess Weight: Weight Trajectory Effects.

Increased risk of type 2 diabetes mellitus (T2D) among individuals with overweight or obesity is well-established; however, questions remain about the temporal dynamics of weight change (gain or loss) on the natural course of T2D in this at-risk population. Existing epidemiologic evidence is limited to studies that discretely sample and assess excess weight and T2D risk at different ages with limited follow-up, yet changes in weight may have time-varying and possibly non-linear effects on T2D risk. Predicting the impact of weight change on the risk of T2D is key to informing primary prevention. We critically review the relationship between weight change, trajectory groups (i.e., distinct weight change patterns), and T2D risk among individuals with excess weight in recently published T2D prevention randomized controlled trials (RCTs) and longitudinal cohort studies. Overall, weight trajectory groups have been shown to differ by age of onset, sex, and patterns of insulin resistance or beta-cell function biomarkers. Lifestyle (diet and physical activity), pharmacological, and surgical interventions can modify an individual's weight trajectory. Adolescence is a critical etiologically relevant window during which onset of excess weight may be associated with higher risk of T2D. Changes in insulin resistance and beta-cell function biomarkers are distinct but related correlates of weight trajectory groups that evolve contemporaneously over time. These multi-trajectory markers are differentially associated with T2D risk. T2D risk may differ by the age of onset and duration of excess body weight, and the type of weight loss intervention. A better understanding of the changes in weight, insulin sensitivity, and beta-cell function as distinct but related correlates of T2D risk that evolve contemporaneously over time has important implications for designing and targeting primary prevention efforts.

Biomarkers and neuromonitoring for prognosis of development after perinatal brain damage

Das sich entwickelnde Gehirn ist in der Perinatalperiode besonders empfindlich für eine Vielzahl von Insulten, wie z. B. Extremfrühgeburtlichkeit und perinatale Asphyxie. Ihre Komplikationen können zu lebenslangen neurokognitiven, sensorischen und psychosozialen Einschränkungen führen; deren Vorhersage bleibt eine Herausforderung. Eine Schlüsselfunktion kommt der möglichst exakten Identifikation von Hirnläsionen und funktionellen Störungen zu. Die Prädiktion stützt sich auf frühe diagnostische Verfahren und die klinische Erfassung der Meilensteine der Entwicklung. Zur klinischen Diagnostik und zum Neuromonitoring in der Neonatal- und frühen Säuglingsperiode stehen bildgebende Verfahren zur Verfügung. Hierzu zählen zerebrale Sonographie, MRT am errechneten Termin, amplitudenintegriertes (a)EEG und/oder klassisches EEG, Nah-Infrarot-Spektroskopie, General Movements Assessment und die frühe klinische Nachuntersuchung z. B. mithilfe der Hammersmith Neonatal/Infant Neurological Examination. Innovative Biomarker und -muster (Omics) sowie (epi)genetische Prädispositionen sind Gegenstand wissenschaftlicher Untersuchungen. Neben der Erfassung klinischer Risiken kommt psychosozialen Faktoren im Umfeld des Kindes eine entscheidende Rolle zu. Eine möglichst akkurate Prognose ist mit hohem Aufwand verbunden, jedoch zur gezielten Beratung der Familien und der Einleitung von frühen Interventionen, insbesondere vor dem Hintergrund der hohen Plastizität des sich entwickelnden Gehirns, von großer Bedeutung. Diese Übersichtsarbeit fokussiert die Charakterisierung der oben genannten Verfahren und ihrer Kombinationsmöglichkeiten. Zudem wird ein Ausblick gegeben, wie innovative Techniken in Zukunft die Prädiktion der Entwicklung und Nachsorge dieser Kinder vereinfachen können.