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Background miRNAs play crucial roles in cancers. This study investigated the potential value of miR-875 to be a detective or/and prognostic marker and evaluate the correlation between its expression and PHH3 index levels in breast cancer. Methods miR-875 expression was determined in breast cancer serum and tissues by a quantitative real-time reverse transcription-polymerase chain reaction. The detective value of serum miR-875 expression for breast cancer was assessed by receiver operating characteristic analysis. Then the associations of miR-875 expression with clinical characteristics of patients and overall survival were evaluated by χ2 test and Kaplan-Meier curve methods, respectively. Results The expression of miR-875 was increased in both breast cancer serum and tissues compared with respective controls. The high miR-875 expression in serum and tissues was associated with positive lymph node metastasis and advanced TNM stages. Besides, miR-875 expression in tissues was positively associated with the PHH3 index. And serum miR-875 could screen breast cancer patients from healthy individuals. Moreover, breast cancer patients with both high expression of miR-875 and PHH3 index had shorter overall survival. Conclusion This study suggested that miR-875 expression may be suitable as a potential breast cancer detection and prognosis biomarker. And the miR-875 expression in tissues was positively associated with the PHH3 index, suggesting that miR-875 expression may be involved in tumor proliferation of breast cancer.

Ferritin is a known inflammatory biomarker in COVID-19. However, many factors and co-morbidities can confound the level of serum ferritin. This current metaanalysis evaluates serum ferritin level in different severity levels in COVID-19. Studies evaluating serum ferritin level in different clinical contexts (COVID-19 vs. control, mild to moderate vs. severe to critical, non-survivor vs. survivor, organ involvement, ICU and mechanical ventilation requirement) were included (total 9 literature databases searched). Metaanalysis and metaregression was carried out using metaphor “R” package. Compared to control (COVID-19 negative), higher ferritin levels were found among the COVID-19 patients [SMD −0.889 (95% C.I. −1.201, −0.577), I2 = 85%]. Severe to critical COVID-19 patients showed higher ferritin levels compared to mild to moderate COVID-19 patients [SMD 0.882 (0.738, 1.026), I2 = 85%]. In meta-regression, high heterogeneity was observed could be attributed to difference in “mean age”, and “percentage of population with concomitant co-morbidities”. Non-survivors had higher serum ferritin level compared to survivors [SMD 0.992 (0.672, 1.172), I2 = 92.33%]. In meta-regression, high heterogeneity observed could be attributed to difference in “mean age” and “percentage of male sex”. Patients requiring ICU [SMD 0.674 (0.515 to 0.833), I2 = 80%] and mechanical ventilation [SMD 0.430 (0.258, 0.602), I2 = 32%] had higher serum ferritin levels compared to those who didn't. To conclude, serum ferritin level may serve as an important biomarker which can aid in COVID-19 management. However, presence of other co-morbid conditions/confounders warrants cautious interpretation.

Despite the common detection of non-donor specific anti-HLA antibodies (non-DSAs) after lung transplantation, their clinical significance remains unclear. In this retrospective single-center cohort study of 325 lung transplant recipients, we evaluated the association between donor specific HLA antibodies (DSAs) and non-DSAs with subsequent CLAD development. DSAs were detected in 30% of recipients and were associated with increased CLAD risk, with higher HRs for both de novo and high MFI (>5000) DSAs. Non-DSAs were detected in 56% of recipients, and 85% of DSA positive tests had concurrent non-DSAs. In general, non-DSAs did not increase CLAD risk in multivariable models accounting for DSAs. However, non-DSAs in conjunction with high BAL CXCL9 levels were associated with increased CLAD risk. Multivariable proportional hazards models demonstrate the importance of the HLA antibody-CXCL9 interaction: CLAD risk increases when HLA antibodies (both DSAs and non-DSAs) are detected in conjunction with high CXCL9. Conversely, CLAD risk is not increased when HLA antibodies are detected with low CXCL9. This study supports the potential utility of BAL CXCL9 measurement as a biomarker to risk stratify HLA antibodies for future CLAD. The ability to discriminate between high versus low-risk HLA antibodies may improve management by allowing for guided treatment decisions.

The involvement of immune checkpoint regulators (ICs) in alcohol-associated liver diseases (ALDs) is still largely unknown. Here, we analyzed the levels of 16 soluble ICs (sICs) in male patients with ALD to determine their clinical significance. The 16 sICs were measured using a luminex-based multiplex assay in 115 patients with ALD and 47 healthy controls (HCs). The expressions of membrane-type (m) PD-1 and mCTLA-4 on CD4+ and CD8+ T lymphocytes and NK cells of 28 patients with ALD and 8 HCs were also measured. Correlation test and risk assessment were also conducted to evaluate biomarkers of ALD in clinical practice. Our results show that four sICs were upregulated (sCTLA-4, sTIM-3, sCD27, and sGITR) and two sICs were downregulated (sLAG-3 and sHVEM) in ALD. mPD-1 expression was significantly more greatly increased on CD4+T lymphocytes in the ALD group than in the HC group (p = 0.009). sTIM-3 was positively correlated, while sLAG-3 was negatively correlated with non-invasive liver fibrosis markers (AST/ALT, APRI, GPR, and FIB-4) and Maddrey discriminant function score. Risk factor analysis showed that sTIM-3 was consistently associated with ALD severity in both MDF and FIB-4 scores, and sLAG-3 was associated with FIB-4 scores. This study revealed the involvement of sCTLA-4, sTIM-3, sCD27, sGITRL, sLAG-3, and sHVEM in discriminating male patients with ALD. Expressions of sTIM-3 and sLAG-3 were correlated with liver fibrosis markers and significantly associated with ALD severity, which can be further studied as diagnostic markers and therapeutic targets in ALD.

Background Interest has mounted into the use of objective clinical biomarkers for traumatic brain injury (TBI). This systematic review and meta-analysis aimed to synthesise the existing evidence investigating the use of serum & plasma biomarkers to exclude significant intracranial injuries seen on CT head scans in patients that present to ED with TBI. Methods The primary outcome was to review the diagnostic accuracy (sensitivity & specificity) of S100B, GFAP and UCH-L1 to exclude significant intracranial pathology on CT head scan in adults presenting with TBI. Secondary outcomes investigated biomarker performance at different time points, in isolated TBI and multi-trauma and with pre-specified cut offs. Systematic searches were conducted on MEDLINE ® (via PubMed), Cochrane electronic databases and EMBASE from 1st January 2000 until June 2020. Bias was assessed using QUADAS 2 tool. A narrative synthesis and meta-analysis were performed. PROSPERO registration number CRD42020212206. Results After screening, 22 papers were included. The total number of patients with TBI was 9,416. There was significant variation regarding study design, population selection and the clinical threshold/decision rule for CT head request. The diagnostic accuracy of S100B as measured by the range of individual sensitivities and specificities were 63-100% and 5-58%, respectively. Individual sensitivities and specificities for GFAP were 67-100% and 0-89% and for UCH-L1 were 61-100% and 21-63.7% respectively. When measured within 3 hours individual sensitivities & specificities for S100B were 98-100% & 20-58% respectively. The quality of evidence for the primary outcome overall was low. The quality of evidence was low for all secondary outcomes apart from studies that used a pre-specified cut off for S100B which had a moderate strength of evidence. Conclusion The overall quality of evidence regarding the diagnostic accuracy of single biomarkers as a rule out for significant intracranial injury seen on CT head scans in ED patients with TBI is low. Based on current evidence, S100B is the only single biomarker with a validated clinical platform, pre-determined cut off threshold and moderate quality evidence; at this stage making it the biomarker of choice. More robust clinical outcome and economic impact data is required to support its incorporation into clinical decision tools.

Aspen and poplar trees are important horticultural plants grown in Canada for aesthetic, commercial woodlot and windbreak applications. Bronze leaf is a destructive disease in Populus spp. and is caused by the fungal pathogen Apioplagiostoma populi Barr. This pathogen is often difficult to isolate and confirm from infected plant tissues and has been mainly identified by disease symptoms and morphological characteristics of A. populi when fruiting bodies form on infected leaves or branches. Affected leaves and branches typically become necrotic and bronze in colour. Air-borne spores and nursery shipments containing infected plants play an important role in the efficient movement of the pathogen. In this study, bronze leaf disease samples from symptomatic trees in Canada were examined microscopically for A. populi perithecia and asci. Pathogen-specific genomic sequences were identified for the development of sensitive stringent diagnostics that indicated branches and petioles were the most effective tissues for detecting A. populi. Leaf samples from symptomatic trees were collected in Canada and examined for perithecia to microscopically characterize A. populi asci and ascospores. Disease associated DNA sequences of the internal transcribed spacer (ITS) 5.8S region of the nuclear ribosomal, β-tubulin 2, and translation elongation factor-1-γ chain, were isolated from perithecia and symptomatic tree samples. Morphological and molecular biological data from this study characterized the relationship and epidemiology of A. populi and enabled the development of rapid diagnostic methods that restrict the extent of further losses in amenity and commercial plantings of aspen and poplar.

Complex diseases are caused by a variety of factors, and their diagnosis, treatment and prognosis are usually difficult. Proteins play an indispensable role in living organisms and perform specific biological functions by interacting with other proteins or biomolecules, their dysfunction may lead to diseases, it is a natural way to mine disease-related biomarkers from protein-protein interaction network. AUC, the area under the receiver operating characteristics (ROC) curve, is regarded as a gold standard to evaluate the effectiveness of a binary classifier, which measures the classification ability of an algorithm under arbitrary distribution or any misclassification cost. In this study, we have proposed a network-based multi-biomarker identification method by AUC optimization (NetAUC), which integrates gene expression and the network information to identify biomarkers for the complex disease analysis. The main purpose is to optimize two objectives simultaneously: maximizing AUC and minimizing the number of selected features. We have applied NetAUC to two types of disease analysis: 1) prognosis of breast cancer, 2) classification of similar diseases. The results show that NetAUC can identify a small panel of disease-related biomarkers which have the powerful classification ability and the functional interpretability.

BACKGROUND: Plasma neurofilament light chain (NfL) is a novel biomarker for age-related neurodegenerative disease. We tested whether NfL may be linked to cardiometabolic risk factors, including BMI, the allostatic load (AL) total score (AL(total)), and related AL continuous components (AL(comp)). We also tested whether these relations may differ by sex or by race. METHODS: We used data from the HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span) study [n = 608, age at visit 1 (v(1): 2004–2009): 30–66 y, 42% male, 58% African American] to investigate associations of initial cardiometabolic risk factors and time-dependent plasma NfL concentrations over 3 visits (2004–2017; mean ± SD follow-up time: 7.72 ± 1.28 y), with outcomes being NfL(v1) and annualized change in NfL (δNfL). We used mixed-effects linear regression and structural equations modeling (SM). RESULTS: BMI was associated with lower initial (γ(01) = −0.014 ± 0.002, P < 0.001) but faster increase in plasma NfL over time (γ(11) = +0.0012 ± 0.0003, P < 0.001), a pattern replicated for AL(total). High-sensitivity C-reactive protein (hsCRP), serum total cholesterol, and resting heart rate at v(1) were linked with faster plasma NfL increase over time, overall, while being uncorrelated with NfL(v1) (e.g., hsCRP × Time, full model: γ(11) = +0.004 ± 0.002, P = 0.015). In SM analyses, BMI's association with δNfL was significantly mediated through AL(total) among women [total effect (TE) = +0.0014 ± 0.00038, P < 0.001; indirect effect = +0.00042 ± 0.00019, P = 0.025; mediation proportion = 30%], with only a direct effect (DE) detected among African American adults (TE = +0.0011 ± 0.0004, P = 0.015; DE = +0.0010 ± 0.00048, P = 0.034). The positive associations between AL(total)/BMI and δNfL were mediated through increased glycated hemoglobin (HbA1c) concentrations, overall. CONCLUSIONS: Cardiometabolic risk factors, particularly elevated HbA1c, should be screened and targeted for neurodegenerative disease, pending comparable longitudinal studies. Other studies examining the clinical utility of plasma NfL as a neurodegeneration marker should account for confounding effects of BMI and AL.

Sea lampreys (Petromyzon marinus) have decimated the Great Lakes fisheries over the past century, and their control is central to protecting native fish populations. Wounding data collected from host fish, including classifying wounds as Type A (penetrating the integument) or Type B (superficial), is an integral part of sea lamprey monitoring efforts and helps inform management decisions; however, wound assessment is subjective and error-prone. This study aimed to determine if protein biomarkers of parasitism could be quantified in host fish plasma to serve as a potential objective aide in current wound assessment practices. Male siscowet lake charr (Salvelinus namaycush) were parasitized in a lab setting for four days, after which the sea lamprey was removed, host blood was collected, and the wound Type recorded. A second blood sample was collected from host fish with Type A wounds 7 months later. The plasma proteome was quantified using iTRAQ, and the relative abundances of 169 proteins were compared between parasitized and non-parasitized control fish. Three functional classes of proteins were modified by sea lamprey parasitism: immune response, lipid transport, and blood coagulation. A major finding was evidence of a concerted anticoagulation response in fish with Type A wounds, including changes in protein components and regulators of fibrin clot formation, some of which did not fully recover within 7 months. A modified clotting assay yielded a smaller thrombin-induced fibrin clot from parasitized fish, supporting the proteomic results. Therefore, measuring blood clottability could improve sea lamprey damage estimates by providing a more objective and quantitative index of parasitism than is offered by wounding data alone.

Asthma-COPD overlap (ACO) is a heterogeneous condition that describes patients who have persistent airflow limitation with clinical features that support both asthma and chronic obstructive pulmonary disease (COPD). Although there is no single consensus definition to diagnose this entity, common major criteria include a strong bronchodilator reversibility or bronchial hyperreactivity, a physician diagnosis of asthma, and ≥ 10 pack-year cigarette smoking history. The prevalence of ACO ranges from 0.9-11.1% in the general population depending on the diagnostic definition used. Notably, patients with ACO have greater symptom burden, worse quality of life, and more frequent and severe respiratory exacerbations than those with asthma or COPD. The underlying pathophysiology of ACO has been debated. While emerging evidence supports the role of environmental and inhalational exposures in its pathogenesis among patients with a pre-existing airway disease, biomarker profiling and genetic analyses suggest ACO may be a heterogeneous condition but with definable characteristics. Early life factors including childhood-onset asthma and cigarette smoking may interact to increase the risk of airflow obstruction later in life. For treatment options, the ACO population has been historically excluded from therapeutic trials; therefore strong, evidence-based recommendations are lacking beyond first-line inhaler therapies. Advanced therapies in patients with ACO are selected according to disease phenotypes and based on extrapolated data from asthma and COPD. Research focused on defining biomarkers and evidence-based treatment options for ACO is urgently needed.

Identification of human miRNAs involved in coronavirus-host interplay is important due to the current COVID-19 pandemic. Therefore, this study aimed to measure the circulating plasma miR-155 expression level in COVID-19 patients and healthy controls to investigate its roles in the pathogenesis and severity of COVID-19 disease and to assess its usefulness as a clinical biomarker for the detection of COVID-19 disease and the severity of infection. A total of 150 COVID-19 patients and 50 controls were enrolled into our study. Beside the routine laboratory work and chest computed tomography (CT) scans of COVID-19 patients, plasma miR-155 expression level was measured using reverse transcription quantitative real-time PCR (RT-qPCR) technique. Our results demonstrated increased miR-155 expression level in COVID-19 patients compared to controls, in severe compared to moderate COVID-19 patients, and in non-survival compared to survival COVID-19 patients. miR-155 expression level also had significant correlation with clinicopathological characteristics of COVID-19 patients such as chest CT findings, CRP, ferritin, mortality, D-dimer, WBC count, and lymphocytes and neutrophils percentages. Also, our results showed that the area under the curve (AUC) for miR-155 was 0.986 with 90% sensitivity and 100% specificity when used as a biomarker for the detection of COVID-19 disease; while in detection of severity of COVID-19 disease, AUC for miR-155 was 0.75 with 76% sensitivity and specificity. From these results we can conclude that miR-155 has a crucial role in the pathogenesis and severity of COVID-19; also, it could be a good diagnostic clinical biomarker for the detection of COVID-19 disease and the severity of infection.

Background/Aims: The residual risk of colectomy after infliximab salvage in steroid-refractory acute severe ulcerative colitis (ASUC) is required to inform the need for subsequent maintenance biologic therapy. The aim of this study was to determine the dynamic response of common serum biomarkers to infliximab salvage and assess their utility in predicting subsequent colectomy.Methods: A retrospective single-center cohort study was conducted on all patients who received infliximab salvage for steroid-refractory ASUC between January 1, 2010, and July 31, 2019. Biomarkers were assessed on admission and days 1 and 3 post infliximab, and included C-reactive protein (CRP)-albumin-ratio (CAR), CRP-lymphocyte-ratio (CLR), platelet-lymphocyte-ratio (PLR) and neutrophil-lymphocyte-ratio (NLR).Results: Of 94 patients (median age, 35 years; 67% of male), 20% required colectomy at 12 months. Biomarkers on day 3 post-infliximab best differentiated nonresponders, who had higher CRP, lower albumin and lower lymphocyte count (each P< 0.05). Day 3 predictive performance (area under the curve) for 12-month colectomy was best for CAR (0.871) and CLR (0.874), which were similar to Lindgren (0.829; P> 0.05) but superior to Mayo (0.726), partial Mayo (0.719), PLR (0.719), Ho index (0.714), NLR (0.675), Travis score (0.657) and endoscopic Mayo (0.609) (each P< 0.05). A day 3 CAR cutoff of 0.47 mg/g had 79% sensitivity, 80% specificity, 94% negative predictive value (NPV) to predict colectomy; while a day 3 CLR cutoff of 6.0 mg/109 had 84% sensitivity, 84% specificity, 96% NPV.Conclusions: CAR and CLR measured on day 3 post infliximab salvage for steroid-refractory ASUC represent simple and routinely performed biomarkers that appear to be strong predictors of colectomy. Prospective studies are required to confirm the utility of these predictive scores.

Circulating tumor mast cells (CTMCs) have been identified in the blood of a small number of patients with advanced systemic mastocytosis (SM). However, data are limited about their frequency and prognostic impact in patients with MC activation syndrome (MCAS), cutaneous mastocytosis (CM) and nonadvanced SM. We investigated the presence of CTMCs and MC-committed CD34+ precursors in the blood of 214 patients with MCAS, CM, or SM using highly sensitive next-generation flow cytometry. CTMCs were detected at progressively lower counts in almost all patients with advanced SM (96%) and smoldering SM (SSM; 100%), nearly half of the patients (45%) with indolent SM (ISM), and a few patients (7%) with bone marrow (BM) mastocytosis but were systematically absent in patients with CM and MCAS (P < .0001). In contrast to CTMC counts, the number of MC-committed CD34+ precursors progressively decreased from MCAS, CM, and BM mastocytosis to ISM, SSM, and advanced SM (P < .0001). Clinically, the presence (and number) of CTMCs in blood of patients with SM in general and nonadvanced SM (ISM and BM mastocytosis) in particular was associated with more adverse features of the disease, poorer-risk prognostic subgroups as defined by the International Prognostic Scoring System for advanced SM (P < .0001) and the Global Prognostic Score for mastocytosis (P < .0001), and a significantly shortened progression-free survival (P < .0001) and overall survival (P = .01). On the basis of our results, CTMCs emerge as a novel candidate biomarker of disseminated disease in SM that is strongly associated with advanced SM and poorer prognosis in patients with ISM.

Цель исследования — оценка контрастно-цветовой чувствительности в центральной области поля зрения, контрастно-частотной чувствительности и динамической остроты зрения у здоровых испытуемых, в больных и здоровых глазах при рассеянном склерозе (РС) у пациентов с перенесенным ретробульбарным оптическим невритом (РБН) и без него. Материал и методы. Исследование зрительных функций проведено в 150 глазах 114 здоровых испытуемых, 49 глазах 36 пациентов с РС, перенесших острый РБН, и 43 глазах 29 пациентов с РС без перенесенного РБН. У всех испытуемых перед исследованием показателей световой чувствительности проводились определение статической остроты зрения, рефракции и офтальмоскопия глазного дна. Результаты и заключение. На основании анализа показателей контрастно-цветовой чувствительности, контрастно-частотной чувствительности и динамической остроты зрения проведена оценка изменений световой чувствительности больных и здоровых глаз у пациентов с РС с перенесенным РБН и без него. Выявлено, что световая чувствительность снижена во вторых — здоровых глазах при РС с перенесенным монокулярным РБН и что снижение световой чувствительности в глазах при РС с перенесенным РБН более глубокое. Световая чувствительность остается сниженной, несмотря на восстановление статической остроты зрения после перенесенного РБН. Различия показателей cветовой чувствительности зрительной системы используются для обсуждения связи острой демиелинизирующей оптической нейропатии с нейрональными повреждениями и характером течения рассеянного склероза. Обсуждается также возможность использования данных о снижении световой чувствительности для ранней диагностики и оценки нейрональных нарушений в зрительной системе при РС.

BACKGROUND The effects of catheter ablation (CA) energy sources on myocardial injury and coagulation biomarkers among Japanese non-valvular atrial fibrillation patients receiving uninterrupted periprocedural edoxaban are unclear. This KYU-RABLE exploratory subanalysis compared the effects of CA using radiofrequency energy vs. cryoballoon on: (1) myocardial injury; and (2) plasma edoxaban and coagulation biomarker concentrations measured before and after CA.Methods and Results:Plasma creatine kinase (CK), edoxaban, D-dimer, and prothrombin fragment 1+2 (F1+2) concentrations within 1 h before CA were compared with concentrations the day after. All biomarkers increased after CA, regardless of the energy source, but especially with cryoballoon. Significantly higher increases in CK concentrations from before to the day after CA were seen with cryoballoon compared with radiofrequency energy (P

Background Low lymphocyte-to-monocyte ratio and high platelet-to-lymphocyte ratio have been reported to be poor prognostic indicators in various solid tumors, but the prognostic significance in rectal cancer remains controversial. Objectives We sought to determine the prognostic value of lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio following curative-intent surgery for rectal cancer. Data sources Following PRISMA guidelines (PROSPERO, ID: CRD42020190880), PubMed and Embase databases were searched through January 2021 including 3 other registered medical databases. Study selection Studies evaluating the impact of pretreatment lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio on overall or disease-free survival in patients undergoing curative rectal cancer resection were selected. Main outcomes measures The main outcome measures were overall and disease-free survival. Results A total of 23 studies (6683 patients) were included; lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio were evaluated in 14 and 16 studies, respectively. Low lymphocyte-to-monocyte ratio was associated with poorer overall survival (HR 1.57, 95% CI 1.29-1.90, P Limitations The retrospective nature of most included studies was a limitation. Conclusions Pretreatment lymphocyte-to-monocyte ratio, but not platelet-to-lymphocyte ratio, correlates with tumor response to neoadjuvant chemoradiotherapy and poorer prognosis after curative-intent surgery for rectal cancer, and it potentially represents a simple and reliable biomarker that could help optimize individualized clinical-decision making in high-risk patients.PROSPERO, ID: CRD42020190880.

Background: Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase located in the centriole of the chromosome during the cell cycle. PLK4 overexpression has been described in a variety of many common human epithelial tumors. Conversely, PLK4 acts as a haploinsufficient tumor suppressor in some situations, highlighting the importance of strict regulation of PLK4 expression, activity, and function. Meanwhile, the importance of chemoradiation resistance in rectal cancer is being emphasized more than ever. We aimed to analyze PLK4 expression and the tumor regression grade (TRG) in patients with rectal cancer, treated with chemoradiotherapy (CRT).Methods: A retrospective study was conducted on 102 patients with rectal cancer who received preoperative CRT. Immunohistochemistry for PLK4 in paraffin-embedded tissue was performed from the biopsy and surgical specimens. Results: We found significant association between high expression of PLK4 and poor response to neoadjuvant CRT (according to both Mandard and The Korean Society of Pathologists TRG systems) in the pre-CRT specimens. Other clinicopathologic parameters did not reveal any correlation with PLK4 expression. Conclusions: This study revealed an association between high expression of PLK4 in the pre-CRT specimens and TRG. Our results indicated that PLK4 could potentially be a new predictor for CRT effect in patients with rectal cancer.

Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Alzheimer's disease (AD) is an accelerating neurodegenerative disorder. Dysfunction of mitochondria and oxidative stress contributes to the pathogenesis of AD. Sirtuins play a role in this pathway and can be a potential marker to study neurodegenerative changes. This study evaluated serum levels of all seven sirtuins (SIRT1 – SIRT7) proteins in three study groups: AD, Mild Cognitive Impairment (MCI), and Geriatric Control (GC) by Surface Plasmon Resonance (SPR) technique. Further, it was validated by the Western blot experiment. ROC analysis was performed to differentiate the study group based on the concentration of serum SIRT proteins. Out of seven sirtuins, serum SIRT1, SIRT3, and SIRT6 levels (mean+SD) were significantly decreased in AD (1.65±0.56, 3.15±0.28, 3.36±0.32ng/µl); compare to MCI (2.17±0.39, 3.60±0.51, 3.73±0.48ng/µl) and GC (2.84±0.47, 4.55±0.48, 4.65±0.55ng/µl). ROC analysis showed the cut-off value with high sensitivity and specificity for cognitive impairment (AD and MCI). The concentration declined significantly with the disease progression. No specific difference was observed in case of other SIRTS between the study groups. This study reveals an inverse relation of serum SIRT1, SIRT3, and SIRT6 concentration with AD. ROC analysis showed that these serum proteins have greater accuracy in diagnosing of AD. This is the first report of estimation of all seven serum sirtuins and the clinical relevance of SIRT3 and SIRT6 as serum protein markers for AD.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies in adults, displaying a progressive, frequently asymmetric involvement of a typical muscles’ pattern. FSHD is associated with epigenetic derepression of the polymorphic D4Z4 repeat on chromosome 4q, leading to DUX4 retrogene toxic expression in skeletal muscles. Identifying biomarkers that correlate with disease severity would facilitate clinical management and assess potential FSHD therapeutics’ efficacy. Objectives: This study purpose was to analyze serum cytokines to identify potential biomarkers in a large cohort of adult patients with FSHD. Methods: We retrospectively measured the levels of 20 pro-inflammatory and regulatory cytokines in sera from 100 genetically confirmed adult FSHD1 patients. Associations between cytokine concentrations and various clinical scores were investigated. We then measured serum and muscle interleukin 6 (IL-6) levels in a validated FSHD-like mouse model, ranging in severity and DUX4 expression. Results: IL-6 was identified as the only cytokine with a concentration correlating with several clinical severity and functional scores, including Clinical Severity Score, Manual Muscle Testing sum score, Brooke and Vignos scores. Further, FSHD patients displayed overall IL-6 levels more than twice high as control, and patients with milder phenotypes exhibited lower IL-6 serum concentration than those with severe muscular weakness. Lastly, an FSHD-like mouse model analysis confirmed that IL-6 levels positively correlate with disease severity and DUX4 expression. Conclusions: Serum IL-6, therefore, shows promise as a serum biomarker of FSHD severity in a large cohort of FSHD1 adult patients.

Periodontitis is a disease of surrounding dental tissue with a prevalence of 74.1% in Indonesia. Many studies show periodontitis plays a role in the progression of atherosclerosis. The relationship between these two conditions shows that scaling root planing intervention can reduce the risk of atherosclerosis. This study aimed to know the efficacy of scaling root planing on changes in inflammatory biomarkers in periodontitis patients with atherosclerosis. This systematic literature review was conducted using the Rapid Review method that refers to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Electronic searches were carried out from 4 electronic databases, including the National Library of Medicine (Medline / PubMed), The Cochrane Library, EbscoHOST, and SAGE Journal. Inclusion and exclusion criteria selected 6 RCT articles to be analyzed qualitatively. Within 2 to 6 months, research in 6 RCT articles showed the results in significantly reducing CRP levels as the main biomarkers of atherosclerosis after scaling root planing intervention. Other biomarkers that were also assessed are cytokines levels, lipid profile components, WBC, and fibrinogen. Overall results showed a positive effect of scaling root planing intervention in reducing the inflammatory biomarker levels of atherosclerosis in periodontitis patients with atherosclerosis. The treatment of scaling root planing is considered effective in reducing the inflammatory biomarker levels of atherosclerosis in periodontitis patients with atherosclerosis to reduce the level of risk. KEYWORDS: scaling root planing, inflammatory biomarker, atherosclerosis

Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer’s disease (AD) diagnosis and treatment. Objective: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts. Methods: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal amyloid negative (n = 6) and positive (n = 5) individuals, and amyloid positive prodromal (n = 13), mild (n = 12), and moderate AD patients (n = 10); and Cohort B included amyloid positive prodromal (n = 24) and mild (n = 40) AD patients. Results: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with SUVR measures from [18F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18F]GTP1 and amyloid PET. Conclusion: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease.

Background: Down syndrome (DS) is associated with increased risk for Alzheimer’s disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS. Objective: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS? Methods: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38–61 years). Results: Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity. Conclusion: Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.

Background Serum lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA) and CYFRA21-1 are the commonly used biomarkers to identify patients with autoimmune pulmonary alveolar proteinosis (APAP). However, it is not clear which of the biomarkers is more sensitive to the severity of the patient’s condition. Methods APAP patients numbering 151 were enrolled in this study. All patients’ severity was assessed through the severity and prognosis score of PAP (SPSP). According to the respective laboratory upper limits of serum levels of LDH, CEA and CYFRA21-1, APAP patients were divided into higher and lower-level groups. Patients were divided into five groups based on SPSP. 88 patients had completed six months of follow-up. We calculated sensitivity, specificity, and critical point of LDH, CEA and CYFRA21-1 between APAP patients and normal control group, and between grade 1–2 and 3–5 through receiving operating characteristics (ROC) curve. Results Serum LDH, CEA and CYFRA21-1 levels of patients with PAP were higher and distinctly related to PaO2, FVC, FEV1, DLCO, HRCT scores and SPSP. The SPSP of patients in higher-level LDH, CEA and CYFRA21-1 groups were higher than those of corresponding lower-level groups. Based on SPSP results, the patients were divided into five groups (grade I, 20; grade II, 37; grade III, 40; grade IV, 38; grade V, 16). The serum level of CYFRA21-1 of patients with APAP in grade II was higher than that of patients in grade I and lower than that of patients in grade III. Serum CYFRA21-1 of patients with APAP after six months were higher than the baseline among the aggravated group. Serum LDH, CEA and CYFRA21-1 levels after six months among patients in the relieved group of patients with APAP were lower than the baseline. ROC correlating LDH, CEA and CYFRA21-1 values with APAP severity (between grade 1–2 and 3–5) showed an optimal cutoff of LDH of over 203 U/L ( 3.3 ng/ml) (AUC: 0.815, 95% CI [0.748–0.882], sensitivity: 0.606, specificity: 0.877). Conclusion Serum CYFRA21-1 level was more sensitive in revealing the severity of APAP than LDH and CEA levels among mild to moderate forms of disease.

Background The management of locally advanced rectal cancer (LARC) requires a multidisciplinary approach, with an increasing interest for non-operative strategies. Liquid biopsy for obtaining circulating tumor DNA (ctDNA) can provide information on neoadjuvant chemoradiotherapy (nCRT) pathological response and cancer-specific prognosis, and therefore might be a promising guide for these treatments. Methods A systematic review of the studies available in literature has been performed to assess the role of ctDNA as a predictive and prognostic biomarker in LARC patients. Results We retrieved 21 publications, of which 17 full-text articles and 4 abstracts. Results have been labelled into two groups: predictive and prognostic. Data about the usefulness of liquid biopsy in this setting is still inconclusive. However, baseline higher levels of longer fragments of cell-free DNA and integrity index, tumor-specific mutations and certain methylated genes could predict non-responders. Also, undetectable baseline ctDNA and decrease of common rectal cancer mutations throughout treatment (dynamic monitoring) were predictive factors of pathological complete response. The continuous detection of ctDNA in different timepoints of treatment (minimal residual disease) was consistently associated with worse prognosis. Conclusions ctDNA is a promising biomarker that could assist predicting treatment response to nCRT and prognosis in patients with LARC. The ideal methods and timings for the liquid biopsy still have to be defined.

The reach of personalized medicine in radiation oncology has expanded greatly over the past few decades as technical precision has improved the delivery of radiation to each patient’s unique anatomy. Yet, the consideration of biological heterogeneity between patients has largely not been translated to clinical care. There are innumerable promising advancements in the discovery and validation of biomarkers, which could be used to alter radiation therapy directly or indirectly. Directly, biomarker-informed care may alter treatment dose or identify patients who would benefit most from radiation therapy and who could safely avoid more aggressive care. Indirectly, a variety of biomarkers could assist with choosing the best radiosensitizing chemotherapies. The translation of these advancements into clinical practice will bring radiation oncology even further into the era of precision medicine, treating patients according to their unique anatomical and biological differences.

Antioxidant defence mechanisms, such as the nuclear factor-erythroid 2-related-factor-2 (NRF2) axis, are integral to oxidative stress responses and ischemic injury. Hepatic antioxidant capacity is contingent on parenchymal quality, and there is a need to develop new insights into key molecular mechanisms in marginal liver allografts that might provide therapeutic targets. This study examines the clinical relevance of NRF2 in donor livers and its response to normothermic machine perfusion (NMP). Discarded donor livers (n = 40) were stratified into a high NRF2 and low NRF2 group by quantifying NRF2 expression. High NRF2 livers had significantly lower transaminase levels, hepatic vascular inflammation and peri-portal CD3+ T cell infiltration. Human liver allografts (n = 8) were then exposed to 6-h of NMP and high NRF2 livers had significantly reduced liver enzyme alterations and improved lactate clearance. To investigate these findings further, we used a rat fatty-liver model, treating livers with an NRF2 agonist during NMP. Treated livers had increased NRF2 expression and reduced transaminase derangements following NMP compared to vehicle control. These results support the association of elevated NRF2 expression with improved liver function. Targeting this axis could have a rationale in future studies and NRF2 agonists may represent a supplemental treatment strategy for rescuing marginal donor livers.

Introduction Colorectal cancer (CRC) is the third most common malignancy worldwide, with the second highest mortality rate among all malignancies. In this review, we describe the current utility of stool diagnostic biomarkers for CRC. Methods We reviewed stool-related tests and biomarker candidates for the diagnosis of CRC. The guaiac-based fecal occult blood test (gFOBT), fecal immunochemical test (FIT), and multitarget stool DNA test (MT-sDNA) have been used as clinical CRC screening tools. Although microRNAs, protein biomarkers, and microbiota have not yet been used in clinical CRC screening, there is growing evidence that they have the potential to function as CRC screening tools. Results According to the literature, the sensitivity of MT-sDNA for detecting CRC was 87.0%-100%, 32.7%-82.0% for advanced adenomas, and the specificity was 86.1%-95.2%. The sensitivity of individual biomarkers of fecal microRNAs for detecting CRC was 34.2%-88.2%, 73.0% for advanced adenomas, and the specificity was 68%-100%. The sensitivity of fecal protein markers for detecting CRC was 63.6-93.0%, 47.7%-69.4% for advanced adenomas, and the specificity was 38.3%-97.5%. The sensitivity of fecal microbiota for detecting CRC was 54.0-100.0%, 32.0%-48.3% for advanced adenomas, and the specificity was 61.3%-90.0%. Conclusion MT-sDNA is the most sensitive CRC screening test, and its sensitivity is the highest for advanced adenomas; however, its detection cost is high. MT-sDNA was more sensitive to CRC and advanced precancerous lesions than FIT, but compared to three years of MT-sDNA, annual FIT as the first non-invasive screening test for CRC seemed to be more effective.

Contains fulltext : 227274.pdf (Publisher’s version ) (Closed access) BACKGROUND Anaesthesia is a stressful medical specialty. The reaction to stress is constituted by behavioural, psychological and physiological components. Chronic physiological stress can have negative consequences for health. OBJECTIVES First, we hypothesised that chronic physiological stress is higher for both beginning and late-career consultant anaesthesiologists. Second, we hypothesised that individuals high in emotional intelligence endure lower physiological stress. DESIGN Cross-sectional biomarker and survey study. SETTING Participants were recruited during the May 2019 annual meeting of the Dutch Anaesthesia Society. PARTICIPANTS Of the 1348 colleagues who attended the meeting, 184 (70 male/114 female) participated in the study. Of the study participants, 123 (67%) were consultant anaesthesiologists (52 male/71 female) and 61 (33%) were resident anaesthesiologists (18 male/43 female). Exclusion criteria were endocrine disorders and not having enough hair. Also, experience of a recent major life event led to exclusion from analysis of our hypotheses. MAIN OUTCOME MEASURES Chronic physiological stress was measured by hair cortisol concentration. Emotional intelligence was assessed using a validated Dutch version of the Trait Emotional Intelligence Questionnaire. As secondary measures, psychological sources of stress were assessed using validated Dutch versions of the home-work interference (SWING) and the effort-reward imbalance questionnaires. RESULTS In support of Hypothesis 1, hair cortisol concentration was highest among early and late-career consultant anaesthesiologists (quadratic effect: b = 45.5, SE = 16.1, t = 2.8, P = 0.006, R2 = 0.14). This nonlinear pattern was not mirrored by self-reported sources of psychological stress. Our results did not support Hypothesis 2; we found no evidence for a relationship between emotional intelligence and physiological stress. CONCLUSION In the early and later phases of an anaesthesiologist's career, physiological chronic stress is higher than in the middle of the career. However, this physiological response could not be explained from known sources of psychological stress. We discuss these findings against the background of key differences between physiological and psychological stress. 7 p.

Background and aims Fecal calprotectin (FC) is a non-invasive biomarker used in inflammatory bowel disease (IBD) management and risk stratification of non-specific gastrointestinal symptoms. Leukocyte esterase is an inexpensive and widely available point-of-care inflammatory marker present on urinalysis test strips. We aim to assess the diagnostic accuracy of fecal leukocyte esterase (FLE) relative to FC and endoscopy and demonstrate its use as an alternative biomarker for IBD. Methods In this prospective cohort study, 70 patients who had FC ordered as part of standard clinical care also received FLE testing. FLE levels were compared to various FC cut-off values and endoscopy and pathology findings as gold standard. Results As the FC cut-off increased from 50 to 500 μg/g, FLE sensitivity increased from 67% to 95% while the specificity decreased from 86% to 76%. The area under the receiver operating characteristic (AUROC) increased from 0.79 to 0.90. An FLE of ≥1+ had the best test characteristics. Amongst patients who underwent endoscopic evaluation, FLE demonstrated an identical sensitivity (75%) and specificity (86%) to FC in predicting endoscopic inflammation. AUROC was 0.80 for FLE and 0.85 for FC with an optimal cut-off of ≥2+ and 301 μg/g, respectively. When used to distinguish between active IBD and no/inactive IBD patients, FLE had a sensitivity of 84% and specificity of 90%, comparable to the 84% and 83%, respectively, of FC. AUROC was 0.88 for FLE and 0.91 for FC with an optimal cut-off of ≥2+ and 145 μg/g, respectively. Conclusion FLE demonstrates adequate correlation and comparable accuracy to FC in predicting endoscopic inflammation and distinguishing between patients with active versus inactive IBD.

Abstract: Early diagnosis and accurate prognosis are significant important challenges against effective treatment of cancer and improving patient’s condition. Hitherto, many research works have tended to focus on the carcinoembryonic antigen (CEA) to detect cancers and estimate the survival rates of patients with multiple cancer types, including colorectal, breast, non-small cell lung, and pancreas cancer. Limited sensitivity and specificity of this traditional tumor marker make it an inappropriate biomarker to diagnose cancer, especially in the early stages while several lines of research have introduced miRNAs as reliable indicators of tumor initiation, development, and therapy response. Indeed, miRNAs have unique properties that provide considerable benefits, such as discriminating benign diseases from malignancies, predicting cancer development and progression, checking sensitivity to treatment, and initial detecting of tumors. This review summarizes the relationships between miRNAs and CEA, the diagnostic significance of CEA in combination with miRNAs, and the distinct advantages of miRNAs over CEA as tumor biomarkers. Advancement in our current understanding of miRNAs is very essential to discover new and effective biomarkers for diagnostic, prognostic, and therapeutic goals of cancer patients.

Background: Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are two major subtypes of Non-Small Cell Lung Cancer (NSCLC). Studies have shown that abnormal expression of glucose transport type 1 (GLUT1) in NSCLC patients has been associated with cancer progression, aggressiveness, and poor clinical outcome. However, the clinical effect of GLUT1 expression on LUAD and LUSC is unclear. Objective: This study aims to learn more about the character of GLUT1 in LUAD and LUSC. Methods: A meta-analysis was performed to evaluate the GLUT1 protein level, and the bioinformatics analysis was used to detect the GLUT1 mRNA expression level, survival differences, and the infiltration abundance of immune cells in samples from TCGA. Meanwhile, functional and network analysis was conducted to detect important signaling pathways and key genes with the Gene Expression Omnibus (GEO) dataset. Results: Our results showed that GLUT1 was over-expressed both in LUAD and LUSC. LUAD patients with high GLUT1 expression had a poor prognosis. Additionally, GLUT1 was related to B cell and neutrophil infiltration of LUAD. In LUSC, GLUT1 was correlated with tumor purity, B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration. The GEO dataset analysis results suggested GLUT1 potentially participated in the p53 signaling pathway and metabolism of xenobiotics through cytochrome P450 and was associated with KDR, TOX3, AGR2, FOXA1, ERBB3, ANGPT1, and COL4A3 gene in LUAD and LUSC. Conclusion: GLUT1 might be a potential biomarker for aggressive progression and poor prognosis in LUAD, and a therapeutic biomarker in LUSC.

Itch, or pruritus, is the uncomfortable sensation underlying the desire to scratch. Itch is a very common complaint in the general population that can result from dermatologic, systemic (eg, renal, hepatobiliary, endocrine), paraneoplastic, neuropathic, and psychogenic etiologies. Chronic itch is associated with significant sleep disturbances and profoundly reduces overall quality of life. Certain populations, including elderly and African Americans, are at increased risk of experiencing heightened burden of itch. Because of the variable clinical presentation and wide-ranging etiologies, itch presents a challenge for clinicians. The initial evaluation should include a complete blood count, with differential, hepatic, renal, and thyroid function testing along with diabetes screening. Further testing should be guided by history and physical examination findings. There should be a heightened concern for underlying malignancy in individuals older than 60 years of age who have a history of liver disease and diffuse itch less than 12 months of duration. For individuals with chronic pruritus of unknown origin, increased blood eosinophils may serve as a biomarker of T helper cell type 2 polarization and response to immunomodulator therapies. In this first part of a 2-part continuing medical education series, we describe the broader epidemiology and specific conditions associated with itch and the clinical presentation and diagnostic workup for patients with itch.

We examined the characteristics of individuals with biomarker evidence of tauopathy but without β-amyloid (Aβ) (A-T+) in relation to individuals with (A+T+) and without (A-T-) evidence of Alzheimer’s disease (AD). We included 561 participants with Aβ and tau PET from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We compared A-T- (n = 316), A-T+ (n = 63), and A+T+ (n = 182) individuals on demographics, amyloid, tau, hippocampal volumes, and cognition. A-T+ individuals were low on apolipoprotein E ɛ4 prevalence (17%) and had no evidence of subtly elevated brain Aβ within the negative range. The severity of tau deposition, hippocampal atrophy, and cognitive dysfunction in the A-T+ group was intermediate between A-T- and A+T+ (all p < 0.001). Tau uptake patterns in A-T+ individuals were heterogeneous, but approximately 29% showed tau deposition in the medial temporal lobe only, consistent with primary age-related tauopathy and an additional 32% showed a pattern consistent with AD. A-T+ individuals also share other features that are characteristic of AD such as cognitive impairment and neurodegeneration, but this group is heterogeneous and likely reflects more than one disorder.

Objective: To identify the relationship between red blood cell distribution width (RDW, %), interleukin-6 (IL-6) (pg/ml), high sensitivity-c-reactive protein (hs-CRP) (mg/l), in-hospital mortality and disease severity among patients with heart failure (HF). Methods: Prospective cohort. We included adults diagnosed with acute non-ischemic HF in 2015. The dependent variables were in-hospital mortality (yes or no) and disease severity. The latter was assessed with the Get With The Guidelines-HF score. We used hierarchical regression models to describe the pattern of association between biomarkers, mortality, and severity. We used the Youden index to identify the best cut-off for mortality prediction. Results: We included 167 patients; the mean age was 72.61 (SD: 11.06). The majority of patients presented with New York Heart Association classification II (40.12%) or III (43.11%). After adjusting for age and gender, all biomarkers were associated with mortality. After adding comorbidities, only IL-6 was associated. The final model with all clinical variables showed no effect from any biomarker. The best cut-off for RDW, hs-CRP and IL-6 for mortality were 14.8, 68.7 and 52.9, respectively. IL-6 presented the highest sensitivity (100%), specificity (75.35%) and area under the curve (0.91). Conclusions: No biomarker is independent from the most important clinical variables; therefore it should not be used for management modifications. Resumo: Objetivo: Identificar a relação entre a amplitude de distribuição dos eritrócitos (ADE, %), IL-6 (pg/nl), hs-PCR (mg/l), mortalidade intra-hospitalar e gravidade da doença em doentes com insuficiência cardíaca (IC). Métodos: Coorte prospetiva. Incluímos adultos com IC aguda de etiologia não isquémica durante o ano de 2015. As variáveis dependentes foram a mortalidade intra-hospitalar (sim ou não) e a gravidade da doença. A última foi avaliada com o score de Get With Guidelines-HF (GWTG-HF). Utilizámos modelos de regressão hierarquizados para descrever o padrão de associação entre os biomarcadores, mortalidade e gravidade. Utilizámos o índice Youden para identificar o melhor cut-off na previsão da mortalidade. Resultados: Foram incluidos 167 doentes. A idade média foi de 72,61 (MS: 11,6). A maioria dos doentes estava em Classe II (40,12%) ou III NYHA (43,11%). Após ajuste para idade e género, todos os biomarcadores se associaram à mortalidade. Após adicionar as comorbilidades, só a IL-6 se associou com mortalidade. O modelo final com todas as variáveis clínicas incluidas não mostrou qualquer efeito de qualquer dos biomarcadores estudados. Os melhor cut-off de ADE, hs-PCR e IL-6 para mortalidade foi de 14,8, 68,7 e 52,9 respetivamente. A IL-6 apresentou a sensibilidade mais elevada (100%), especificidade (75,35%) e área sob a curva (0,91). Conclusões: Nenhum dos biomarcadores analisados se revelou independente das variáveis clínicas mais importantes, pelo que os biomarcadores estudados não devem ser utilizados como orientação clínica.

Objectives To assess the ability of the biomarkers neuron-specific enolase (NSE), tau, neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) to predict postoperative cognitive dysfunction (POCD) at discharge in patients who underwent cardiac surgery. Design Post hoc analyses (with tests being prespecified before data analyses) from a randomized clinical trial. Setting Single-center study from a primary heart center in Denmark. Participants Adult patients undergoing elective or subacute on-pump coronary artery bypass grafting and/or aortic valve replacement. Interventions Blood was collected before induction of anesthesia, after 24 hours, after 48 hours, and at discharge from the surgical ward. The International Study of Postoperative Cognitive Dysfunction test battery was applied to diagnose POCD at discharge and after three months. Linear mixed models of covariance were used to assess whether repeated measurements of biomarker levels were associated with POCD. Receiver operating characteristic (ROC) curves were applied to assess the predictive value of each biomarker measurement for POCD. Measurements and Main Results A total of 168 patients had biomarkers measured at baseline, and 47 (28%) fulfilled the POCD criteria at discharge. Patients with POCD at discharge had significantly higher levels of tau (p = 0.02) and GFAP (p = 0.01) from baseline to discharge. The biomarker measurements achieving the highest area under the ROC curve for prediction of POCD at discharge were NFL measured at discharge (AUC, 0.64; 95% confidence interval [CI], 0.54-0.73), GFAP measured 48 hours after induction (AUC, 0.64; 95% CI, 0.55-0.73), and GFAP measured at discharge (AUC, 0.64; 95% CI, 0.54-0.74), corresponding to a moderate predictive ability. Conclusions Postoperative serum levels of tau and GFAP were significantly elevated in cardiac surgery patients with POCD at discharge, however, the biomarkers achieved only modest predictive abilities for POCD at discharge. Postoperative levels of NSE were not associated with POCD at discharge.

Purpose: The purpose of this study was to investigate the incidence of short-term atherosclerosis in the common carotid arteries following radiotherapy.Methods: The mean radiation dose to the arteries was 49.30±15.83 Gy. A computational ultrasound method was introduced to investigate the elastic modulus. Ultrasonography was performed 2-3 cm inferior to the bifurcation region before and after radiotherapy, and sequential images were extracted from a video of each artery. Instantaneous movement of the arterial wall in the radial and longitudinal directions was extracted by implementing the maximum gradient and block matching algorithms, respectively.Results: There was a significant change in systolic blood pressure after radiotherapy (P=0.008). Irradiated arteries had significantly smaller systolic and end-diastolic diameters than non-irradiated arteries (P

VISSER, K., M. Koggel, J. Blaauw, H.J.v.d. Horn, B. Jacobs, and J.v.d. Naalt. Blood based biomarkers of inflammation in mild traumatic brain injury: A systematic review. NEUROSCI BIOBEHAV REV XX(X) XXX-XXX, 2021. – Inflammation is an important secondary physiological response to traumatic brain injury (TBI). Most of the current knowledge on this response is derived from research in moderate and severe TBI. In this systematic review we summarize the literature on clinical studies measuring blood based inflammatory markers following mild traumatic brain injury (mTBI) and identify the value of inflammatory markers as biomarkers. Twenty-three studies were included. This review suggests a distinct systemic inflammatory response following mTBI, quantifiable within 6 hours up to 12 months post-injury. Interleukin-6 is the most promising biomarker for the clinical diagnosis of brain injury while interleukin-10 is a potential candidate for triaging CT scans. The diagnostic and prognostic utility of inflammatory markers may be more fully appreciated as a component of a panel of biomarkers. However, discrepancies in study design, analysis and reporting make it difficult to draw any definite conclusions. For the same reasons, a meta-analysis was not possible. We provide recommendations to follow standardized methodologies to allow for reproducibility of results in future studies.

Background and aims C-reactive protein (CRP) is a hepatocyte-produced marker of inflammation yet with undefined function in liver injury. We aimed to examine the role of CRP in acetaminophen-induced liver injury (AILI). Methods The effects of CRP in AILI were investigated using CRP knockout mice and rats combined with human CRP rescue. The mechanisms of CRP action were investigated in vitro and in mice with Fcγ receptor 2B knockout, C3 knockout, or hepatic expression of CRP mutants defective in complement interaction. The therapeutic potential of CRP was investigated by intraperitoneal administration at 2 or 6 hours post–AILI induction in wild-type mice. Results CRP knockout exacerbated AILI in mice and rats, which could be rescued by genetic knock-in, adeno-associated virus–mediated hepatic expression or direct administration of human CRP. Mechanistically, CRP does not act via its cellular receptor Fcγ receptor 2B to inhibit the early phase injury to hepatocytes induced by acetaminophen; instead, CRP acts via factor H to inhibit complement overactivation on already injured hepatocytes, thereby suppressing the late phase amplification of inflammation likely mediated by C3a-dependent actions of neutrophils. Importantly, CRP treatment effectively alleviated AILI with a significantly extended therapeutic time window than that of N-acetyl cysteine. Conclusion Our results thus identify CRP as a crucial checkpoint that limits destructive activation of complement in acute liver injury, and we argue that long-term suppression of CRP expression or function might increase the susceptibility to AILI.

We aimed to evaluate the optical coherence tomography(OCT) findings and oxidative stress parameters in patients with bipolar disorder(BD) and their unaffected first-degree relatives(FDRs) and to explore OCT findings and oxidative stress parameters as potential endophenotype candidates.Fifty patients with BD, 40 FDRs of BD, and 50 healthy controls(HCs) were included. OCT was performed to measure peripapillary retinal nerve fiber layer(RNFL), ganglion cell layer(GCL), inner plexiform layer(IPL), central macular, and minimum foveal thicknesses(CMT and MFT), choroidal thickness(ChT). 4-hydroxy-2-nonenal(HNE), total thiol(TT), native thiol(NT), total oxidant status(TOS), total antioxidant status(TAS), disulfide(DIS) and oxidative stress index(OSI) were measured from serum samples.TOS was higher patients with BD and FDRs than HCs (p .001 and p = .012, respectively). OSI, DIS, HNE levels were higher patients with BD and FDRs than HCs (p .001). TAS, TT, NT levels were lower patients and FDRs than HCs (p .001). MFT of patients was thinner than HCs (p = .001). CMT of patients was thinner than HCs (p = .006); the same trend was observed in FDRs but did not reach the statistical significance level (p = .07). The groups did not differ on RNFL and choroidal thickness or GCL and IPL volume.Evaluation of only a few retinal layers.TOS, TAS, OSI, TT, NT, DIS, HNE can be useful endophenotype biomarkers in BD. Among the OCT findings, CMT was determined as the closest parameter to being an endophenotype biomarker. Our study corroborates that oxidative stress parameters are more effective than OCT findings in endophenotype studies.

ObjectiveGastric cancer (GC) is the fifth most common malignancy and the fourth leading cause of cancer-related mortality worldwide. The identification of valuable predictive signatures to improve the prognosis of patients with GC is becoming a realistic prospect. DNA damage response-related long noncoding ribonucleic acids (drlncRNAs) play an important role in the development of cancers. However, their prognostic and therapeutic values remain sparse in gastric cancer (GC). MethodsWe obtained the transcriptome data and clinical information from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohort. Co-expression network analyses were performed to discover functional modules using the igaph package. Subsequently, lncRNA pairs were identified by bioinformation analysis, and prognostic pairs were determined by univariate analysis, respectively. In addition, we utilized least absolute shrinkage and selection operator (LASSO) cox regression analysis to construct the risk model based on lncRNA pairs. Then, we distinguished between the high- or low- risk groups from patients with GC based on the optimal model. Finally, we reevaluated the association between risk score and overall survival, tumor immune microenvironment, specific tumor-infiltrating immune cells related biomarkers, and the sensitivity of chemotherapeutic agents. Results32 drlncRNA pairs were obtained, and a 17-drlncRNA pairs signature was constructed to predict the overall survival of patients with GC. The ROC was 0.797, 0.812 and 0.821 at 1, 2, 3 years, respectively. After reclassifying these patients into different risk-groups, we could differentiate between them based on negative overall survival outcome, specialized tumor immune infiltration status, higher expressed immune cell related biomarkers, and a lower chemotherapeutics sensitivity. Compared with previous models, our model showed better performance with a higher ROC value. ConclusionThe prognostic and therapeutic signature established by novel lncRNA pairs could provide promising prediction value, and guide individual treatment strategies in the future.

Background Early identification and treatment of clinical high-risk for psychosis (CHR P) are critical to prevent the onset of psychosis, but there is no objective biomarker for CHR-P diagnosis. Methods Ninety medication naive CHR-P subjects and eighty-six healthy controls (HCs) were recruited. The metabolic profiles of plasma samples were acquired using an untargeted metabolomics approach based on ultra-high-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry. The obtained data were further mapped on the Kyoto Encyclopedia of Genes and Genomes for pathway analysis, and an ensemble learning method was applied to identify diagnostic biomarkers. Bayesian linear regression model was then used to explore predicative biomarkers of conversion to psychosis. Receiver-operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic or predicative value of potential biomarkers. Results A total of one hundred and four differential metabolites and forty-eight differential pathways were identified. A panel of five metabolites was found that could effectively discriminate CHR-P from HCs with area under the ROC curve of 1 in the training set (70% of the samples) and 0.997 in the testing set (30% of the samples). The biosynthesis of unsaturated fatty acids pathway perturbed most significantly in CHR-P subjects. Twenty-three CHR-P subjects converted to psychotic disorders during two-year follow-up, and increased 1-stearoyl-2-arachidonoyl-sn-glycerol in plasma was potentially associated with the higher risk of conversion to psychosis. Conclusions These findings demonstrate the alterations of plasma metabolic profiles in CHR-P population, which may deliver valuable biomarkers for early identification and outcome prediction of CHR-P.

Aim of the work: To assess serum collagen triple helix repeat containing 1 (CTHRC1) protein level in rheumatoid arthritis (RA) patients and compare it with healthy controls. In addition, to evaluate the relation of its level with RA activity and severity Patients and methods: The study included 60 adult RA patients and 60 matched controls. Disease activity score (DAS28), modified health assessment questionnaire (MHAQ) and RA medical records-based index of severity (RARBIS) were assessed in RA patients. Serum CTHRC1 levels were measured in patients and controls by enzyme linked immunosorbent assay (ELISA) Results: They were 49 females and 11 males patients with a mean age of 43.6 ± 10.8 years and disease duration of 8.8 ± 0.9 years. The mean of DAS28 was 4.9 ± 2 (1.95–8.6). Serum CTHRC1 levels were significantly higher in patients than controls (1009.5 ± 79.4 vs. 470.7 ± 8.2 ng/ml, p 583.5 ng/ml with sensitivity of 98.3% and specificity of 100%. CTHRC1 significantly correlated with DAS28 (r = 0.81, p

The incidence of papillary thyroid carcinoma (PTC) is increasing worldwide. The biomarkers to identify aggressive types of PTC are limited, illustrating the need to establish reliable novel biomarkers. Protein disulfide isomerase A3 (PDIA3) is a chaperone protein that modulates the folding of newly synthesized glycoproteins and stress-responsive proteins in the endoplasmic reticulum. Although the role of PDIA3 in various cancers such as breast, uterine cervix, head and neck, and gastrointestinal tract has been examined, its expression in thyroid cancer has not been reported. We retrospectively reviewed accumulated data with long-term follow-up of 1,139 PTC patients, and investigated the correlation between immunohistochemical expression of PDIA3 in PTC patients and clinicopathological features and prognosis. PDIA3 expression was significantly lower in PTCs compared to normal thyroid tissues (NTT; n = 80, p = 0.002). In PTCs, correlation between low PDIA3 expression and lymph node metastasis (p = 0.018) and the number of positive nodes (p = 0.004) was observed. Patients with low PDIA3 expression exhibited worse cause-specific survival compared to those with high PDIA3 expression (p = 0.013). Our findings indicate that low PDIA3 expression is related to poor clinical outcome in PTC patients, and that PDIA3 may potentially be a novel ancillary biomarker. Further clarification of the biological role of PDIA3 in PTC is warranted for the future clinical application.

Background/Aims: Anti-phospholipase A2 receptor (PLA2R) autoantibody is the main biomarker of idiopathic membranous nephropathy (IMN). We aimed to find a new cutoff value of anti-PLA2R for patients with IMN and to explore the relevance between this antibody and baseline clinical parameters.Methods: A total of 670 subjects including 374 IMN cases and 296 non-IMN controls were included between January 2017 and January 2020. All clinical parameters were collected at the time of renal biopsy. The levels of anti-PLA2R were detected by a commercial enzyme-linked immunosorbent assay (ELISA) kit. The optimal cutoff value was calculated by a receiver operating characteristic curve and compared in diagnostic efficiency.Results: The optimal cutoff value of anti-PLA2R for IMN was 7.45 RU/mL with the highest Youden index, and the corresponding sensitivity, specificity, positive predictive value and negative predictive value were 80.75%, 97.97%, 98.05% and 80.11%, respectively. Anti-PLA2R levels in IMN patients demonstrated a significant positive correlation with serum creatinine and 24-hour urinary protein, while they showed a negative correlation with serum albumin and estimated glomerular filtration rate.Conclusions: The recommended cutoff value of anti-PLA2R is 7.45 RU/mL using ELISA detection for distinguishing IMN from non-IMN nephropathy. The level of anti-PLA2R is related to baseline renal function in IMN. This new threshold can improve the diagnostic efficiency and facilitate early diagnosis of IMN.

In this study, we investigated the changes in global methylation status and its functional relevance in childhood atopic dermatitis (AD). Differences in epigenome-scale methylation events in peripheral blood associated with childhood AD were screened using DNA methylation arrays of 24 patients with AD compared with 24 control subjects. Of the 16,840 differentially methylated CpG regions between AD and control subjects, >97% CpG loci revealed hypomethylation in patients with childhood AD. Among the globally hypomethylated loci, we identified two CpG clusters within the golli-mbp locus of the MBP gene, which was functionally enriched by subnetwork enrichment analysis as an orchestrator among associated genes. The differential hypomethylation of the top-ranked cg24700313 cluster in the golli-mbp locus was validated by pyrosequencing in an independent cohort of 224 children with AD and 44 control subjects. DNA methylation was found to be negatively correlated with disease severity but showed no significant correlation with IgE levels after age adjustment. The multivariate correlation analysis represents a higher score in AD intensity with significantly increased IgE levels and decreased methylation levels in cg27400313. We concluded that methylation loss in the golli-mbp locus is an epigenetic factor associated with disease severity of childhood AD.

The clinical research on BH4 is limited because of the difficulties on its measurement. In this study, we used our own established LC-MS/MS method to examine the plasma BH4 levels in diabetes to determine whether it could be used as a biomarker for the prediction of kidney injury in those patients.Hospitalized diabetes patients in Renmin Hospital of Wuhan University from Jan to Aug 2021 were recruited. To assess the association between plasma BH4 with ACR or eGFR in diabetes, a total of 142 patients with type 2 diabetes (T2DM) were enrolled. They were divided into three groups by albuminuria levels: normoalbuminuria (n = 68), microalbuminuria (n = 48), and macroalbuminuria (n = 26) according to ACR; or into two groups by eGFR: eGFR≥90 or eGFR90 ml/min for correlation and logistic regression analysis. Plasma BH4 level was measured by LC-MS/MS along with other biochemical indices.Plasma BH4 concentrations were decreased as ACR progressed. BH4 (r = -0.55, P 0.001) and 2h C-Peptide (CP-2h) (r = -0.248, P = 0.003) levels were negatively correlated with ACR. Moreover, multivariable logistic regression analysis showed BH4 concentrations (B = -0.468, P 0.001) and CP-2h (B = -0.257, P = 0.028) were independently associated with ACR progression. ROC curve showed that BH4 level has a predictive value on ACR (95%CI 0.686-0.841, sensitivity 69.1%, specificity 73%). Moreover, in diabetes patients with eGFR≥90 ml/min, plasma BH4 level (P = 0.008) is higher than those in diabetes with eGFR90 ml/min and BH4 was remained independently associated with eGFR after multivariable logistic regression analysis (B = -0.193, P = 0.048).Our established LC-MS/MS method could be used on human plasma BH4 measurements and our data suggested that BH4 level can be used as a biomarker for kidney injury in diabetes indicated by its association with ACR progression and early renal function decline.

A highly sensitive time-resolved fluorescence lateral flow immunoassay (TRF-LFIA) was developed to quantify glial fibrillary acidic protein (GFAP), a trauma brain injury (TBI) biomarker in blood, for the purpose of providing a diagnosis of mild brain injury.