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BackgroundBreast cancer is the most common malignancy among Iranian women. In recent years, the study of dysfunction in the expression of cell-cell junction genes and the related proteins in the malignant process has been at the center of attention. MethodsIn this study, 50 patients were selected who had both cancerous tissue and adjacent healthy tissue. The expression of the desmoglein 2 gene was evaluated. Healthy and cancerous tissue were compared using routine hematoxylin and eosin staining. The total protein was also compared between these two groups. The ultrastructural examination was performed.ResultsThe real-time polymerase chain reaction results showed a decrease in the expression of the desmoglein 2 gene in all tumor samples compared to the healthy samples (p-value ConclusionOverall, the findings showed that the association between desmoglein 2 gene expression and alterations in cellular connections leads to impaired cellular connections, which is an important risk factor for breast cancer. This result proposed the understudy gene as a new biomarker in the development of breast cancer.

We performed a retrospective analysis of the patients assessed at our memory unit for whom Alzheimer disease (AD) cerebrospinal fluid biomarker results were available. We selected patients diagnosed with mild cognitive impairment due to AD (National Institute on Aging-Alzheimer's Association clinical criteria), confirmed neuropsychological deficit, a Global Deterioration Scale score of 3, and an abnormal profile of cerebrospinal fluid biomarkers. Of the 588 cases reviewed, 110 met the inclusion criteria. During follow-up, 50 cases (45.45%) progressed to dementia due to AD. Baseline levels of total and phosphorylated tau were higher in the group of patients that progressed to dementia than in those remaining with mild cognitive impairment. After adjusting for age, sex, history of hypertension, diabetes, and educational level, a 10% increase in total tau protein values was associated with a 7.60% increase in the risk of progression to dementia (hazard ratio: 2.22; 95% confidence interval, 1.28-3.84]; P = .004). Among patients with mild cognitive impairment due to AD and abnormal cerebrospinal fluid biomarker profiles, progressively higher concentrations of total or phosphorylated tau were associated with increased risk of progression to dementia.

Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either: (a) a single episode of exercise (166 samples from 83 individuals) or (b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).Two miRNAs (miR-532-5p, miR-182-5p) decreased (adjusted p0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p, miR-29c-3p) were associated (R0.50; adjusted p0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adjusted p0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (AUC0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).Salivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment.

Background Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a high mortality rate and poor prognosis. miR-637 has been reported to regulate tumor progression and act as a prognosis biomarker of various cancers. Its functional role in NSCLC was investigated in this study. Methods The expression level of miR-637 in NSCLC tissues and adjacent normal tissues of 123 NSCLC patients was analyzed by qRT-PCR. The association between miR-637 and clinical pathological features in the prognosis of patients was analyzed. Cell transfection was performed to overexpress or knockdown miR-637 in H1299 and HCC827. The proliferation, migration, and invasion of H1299 and HCC827 were evaluated by CCK8 and Transwell assay. Results miR-637 expression was significantly decreased in NSCLC tissues and cell lines relative to normal tissues and cells. The survival rate of NSCLC patients with low miR-637 expression was lower than that of patients with high miR-637 expression. Additionally, miR-637 served as a tumor suppressor that inhibited cell proliferation, migration, and invasion of NSCLC. Conclusion Downregulation of miR-637 in NSCLC was associated with TNM stage and poor prognosis of patients and served as a tumor suppressor in NSCLC. These results provide a potential strategy to control NSCLC.

Background Individualized and reliable biomarkers are crucial for diagnosing Alzheimer’s disease (AD). However, lack of accessibility and neurobiological correlation are the main obstacles to their clinical application. Machine learning algorithms can effectively identify personalized biomarkers based on the prominent symptoms of AD. Methods Episodic memory–related magnetic resonance imaging (MRI) features of 143 patients with amnesic mild cognitive impairment (MCI) were identified using a multivariate relevance vector regression algorithm. The support vector machine classification model was constructed using these MRI features and verified in 2 independent datasets (N = 994). The neurobiological basis was also investigated based on cognitive assessments, neuropathologic biomarkers of cerebrospinal fluid, and positron emission tomography images of amyloid-β plaques. Results The combination of gray matter volume and amplitude of low-frequency fluctuation MRI features accurately predicted episodic memory impairment in individual patients with amnesic MCI (r = .638) when measured using an episodic memory assessment panel. The MRI features that contributed to episodic memory prediction were primarily distributed across the default mode network and limbic network. The classification model based on these features distinguished patients with AD from normal control subjects with more than 86% accuracy. Furthermore, most identified episodic memory–related regions showed significantly different amyloid-β positron emission tomography measurements among the AD, MCI, and normal control groups. Moreover, the classification outputs significantly correlated with cognitive assessment scores and cerebrospinal fluid pathological biomarkers' levels in the MCI and AD groups. Conclusions Neuroimaging features can reflect individual episodic memory function and serve as potential diagnostic biomarkers of AD.

Background: Although exposure to stings has been identified as the leading risk factor for anaphylaxis due to Hymenoptera venom allergy, professional beekeepers receive hundreds of stings yearly without developing systemic reactions. Objective: This study aims to analyze the mechanisms underlying bee venom tolerance in beekeepers. Methods: A cross-sectional study was conducted. Participants were recruited and classified into 3 groups: allergic patients (APs), who experienced systemic reactions after bee stings, with a positive intradermal test and specific IgE (sIgE) to Apis mellifera venom (AmV); tolerant beekeepers (TBKs), who received ≥50 stings/year; and healthy nonexposed controls (HCs). We measured serum levels of sIgE and specific IgG4 (sIgG4) to AmV, rApi m 1, rApi m 2, rApi m 3, Api m 4, rApi m 5, and rApi m10, as well as AmV-induced basophil degranulation, percentage of T-cell subsets, regulatory T cells (Treg), and IL-10 production. Results: Compared with TBKs, APs had high levels of sIgE to AmV and all its allergic components (P

Aims Although soluble interleukin 2 receptor (sIL‐2R) is a potentially useful biomarker in the diagnosis and evaluation of disease severity in patients with sarcoidosis, its prognostic implication in patients with cardiac sarcoidosis (CS) is unclear. We sought to investigate whether sIL‐2R was associated with clinical outcomes and to clarify the relationship between sIL‐2R levels and disease activity in patients with CS. Methods and results We examined 83 consecutive patients with CS in our hospital who had available serum sIL‐2R data between May 2003 and February 2020. The primary outcome was a composite of advanced atrioventricular block, ventricular tachycardia or ventricular fibrillation, heart failure hospitalization, and all‐cause death. Inflammatory activity in the myocardium and lymph nodes was assessed by 18F‐fluorideoxyglucose positron emission tomography/computed tomography. During a median follow‐up period of 2.96 (IQR 2.24–4.27) years, the primary outcome occurred in 24 patients (29%). Higher serum sIL‐2R levels (>538 U/mL, the median) were significantly related to increased incidence of primary outcome (P = 0.037). Multivariable Cox regression analysis showed that a higher sIL‐2R was independently associated with an increased subsequent risk of adverse events (HR 3.71, 95% CI 1.63–8.44, P = 0.002), even after adjustment for significant covariates. sIL‐2R levels were significantly correlated to inflammatory activity in lymph nodes (r = 0.346, P = 0.003) but not the myocardium (r = 0.131, P = 0.27). Conclusions Increased sIL‐2R is associated with worse long‐term clinical outcomes accompanied by increased systemic inflammatory activity in CS patients.

Context: We previously reported positive behavioral effects of both daily mantra meditation and classical music listening interventions in breast cancer survivors with cancer related cognitive complaints. Objective: The objective of this pilot study was to compare the effects of the meditation intervention to a music listening intervention on biomarkers of inflammation and cellular aging (secondary outcomes) in breast cancer survivors. Design: Randomized control trial, baseline data collection (time 1), post intervention data collection (time 2) Setting: Community-based, Central Texas Participants: 25 breast cancer survivors (BCS) who were 3 months to 6 years post chemotherapy completion and reported cognitive decline Intervention(s): Kirtan Kriya meditation (KK) or music listening (ML), 8 weeks, 12 minutes a day Main Outcome: Telomerase activity [TA], c-reactive protein [CRP], soluble IL-2 receptor alpha [sIL-2Rα], soluble IL-4 receptor [sIL-4R], soluble IL-6 receptor [sIL-6R], soluble tumor necrosis factor receptor II [sTNF-RII], VEGF receptor 2 [sVEGF-R2], and VEGF receptor 3 [sVEGF-R3] Results: Repeated measures analysis of variance models were analyzed from time 1 to time 2 by group for each biomarker. A pattern of greater telomerase activity across time in both groups (F (1,15) = 3.98, p = .06, η²p = .21); significant decreases in sIL-4R across time for both groups (F (1,22)= 6.28, p = .02, η²p = .22); group*time effect was nominally different but not statistically different for sIL-4R (F(1,22)= 3.82, p = .06, η²p = .15); and a pattern for a group*time effect with ML group showing higher levels of sVEGF-R3 at time 2 (F (1,20)=, p = .12, η²p = .11). No significant effects were found for CRP, sIL-2Rα, sIL-6R, sTNF-RII, or sVEGF-R2.

OBJECTIVE: Variability of Cardiovascular disease (CVD) risk, including racial difference, is not fully accounted for by the variability of traditional CVD risk factors. We used a multiple biomarker model as a framework to explore known racial differences in CVD burden. DESIGN: We measured associations between accelerated aging (AccA) measured by a combination of biomarkers, and cardiovascular morbidity and all-cause mortality using data from the Coronary Artery Risk Development in Young Adults study (CARDIA). AccA was defined as the difference between biological age, calculated using biomarkers with the Klemera and Doubal method, and chronological age. Using logistic regression, we assessed overall and race-specific associations between AccA, CVD, and all-cause mortality. RESULTS: Among our cohort of 2959 Black or White middle-aged adults, after adjustment, a one-year increase in AccA was associated with increased odds of CVD (Odds Ratio (OR) = 1.04; 95% CI: 1.02, 1.06), stroke (OR = 1.12; 95% CI: 1.07, 1.17), and all-cause mortality (OR = 1.05; 95% CI: 1.02, 1.08). We did not find significant overall racial differences, but we did find race by sex differences where Black men differed markedly from White men in the strength of association with CVD (OR = 1.06, 95% CI: 1.01, 1.12). CONCLUSIONS: We provide evidence that AccA is associated with future CVD.

Background Tuberculosis (Tb) is a disease with worldwide presence and a major cause of death in several developing countries. Current diagnostic methodologies often lack specificity and sensitivity, whereas a long time is needed to obtain a conclusive result. Material and methods In an effort to develop better diagnostic methods, this study aimed at the discovery of a biomarker signature for Tb diagnosis using a Nuclear Magnetic Resonance based metabolomics approach. In this study, we acquired 1H NMR spectra of blood serum samples of groups of healthy subjects, individuals with latent Tb and of patients with pulmonary and extra-pulmonary Tb. The resulting data were treated with uni- and multivariate statistical analysis. Results/Conclusion Six metabolites (inosine, hypoxanthine, mannose, asparagine, aspartate and glutamate) were validated by an independent cohort, all of them related with metabolic processes described as associated with TB infection. The findings of the study are according with the WHO Target Product Profile recommendations for a triage test to rule-out active TB.

Esophageal squamous cell carcinoma (ESCC) is a major histological subtype of esophageal cancer with a poor prognosis. Although several serum metabolomic investigations have been reported, ESCC tumor-associated metabolic alterations and predictive biomarkers in sera have not been defined. Here, we enrolled 34 treatment-naive patients with ESCC and collected their pre- and post-esophagectomy sera together with the sera from 34 healthy volunteers for a metabolomic survey. Our comprehensive analysis identified ESCC tumor-associated metabolic alterations as represented by a panel of 12 serum metabolites. Notably, postoperative abrosia and parenteral nutrition substantially perturbed the serum metabolome. Furthermore, we performed an examination using sera from carcinogen-induced mice at the dysplasia and ESCC stages and identified three ESCC tumor-associated metabolites conserved between mice and humans. Notably, among these metabolites, the level of pipecolic acid was observed to be progressively increasing in mouse sera from dysplasia to cancerization, and it could be used to accurately discriminate between mice at the dysplasia stage and healthy control mice. Furthermore, this metabolite is essential for ESCC cells to restrain oxidative stress-induced DNA damage and cell proliferation arrest. Together, this study revealed a panel of 12 ESCC tumor-associated serum metabolites with potential for monitoring therapeutic efficacy and disease relapse, presented evidence for refining parenteral nutrition composition, and highlighted serum pipecolic acid as an attractive biomarker for predicting ESCC tumorigenesis.

Abstract. Because its secretion is changed in cerebrospinal fluid and peripheral blood, the neuronal polypeptide VGF (nonacronymic) has been discussed as a biomarker for neuropsychiatric disorders. We have shown an enhanced VGF expression by T-cells from Alzheimer’s disease (AD) patients. In this study, we investigated the VGF expression by peripheral monocytes in 38 AD patients, 5 patients with vascular dementia (VD), and 20 neuropsychiatrically healthy individuals using flow cytometry. We determined an enhanced number of VGF-expressing monocytes in VD patients compared to AD patients. VGF+CD14+ monocytes were not correlated with age, body mass index, Mini-Mental State Examination (MMSE), or Q albumin. These preliminary data support findings indicating that VGF might play a role as a peripheral biomarker in VD.

Telomere length (TL) is a biomarker of cellular proliferative history. In healthy individuals, leukocyte TL shortens with age and associates with the lifespan of men and women. However, most of studies had used linear regression models to address the association of the TL attrition, aging and sex.We evaluated the association between the TL, aging and sex in a cohort of 180 healthy subjects by quantile regression. The TL of nucleated blood cells was measured by fluorescent in situ hypridization (flow-FISH) in a cohort of 89 men, 81 women, and 10 umbilical cord samples. The results were validated by quantitative polymerase chain reaction (qPCR) and compared to a linear regression analysis.By quantile regression, telomere dynamics slightly differed between sexes with aging: women had longer telomeres at birth and slower attrition rate than men until the sixth decade of life; after that, TL eroded faster and became shorter than that in men. These differences were not observed by linear regression analysis, as the overall telomere attrition rates in women and men were similar (42 pb per year, p 0.0001 vs. 45 pb kb per year, p 0.0001). Also, qPCR did not recapitulate flow-FISH findings, as the telomere dynamics by qPCR followed a linear model.The quantile regression analysis accurately reproduced a third-order polynomial TL attrition rate in both women and men, but it depended on the technique applied to measure TL. The Flow-FISH reproduced the expected telomere dynamics through life and, differently from the qPCR, was able to detect the subtle TL variations associated with sex and aging.

BACKGROUND Elevated preoperative plasma levels of the angiogenesis-related marker VEGF have been associated with worse oncological outcomes in various malignancies. OBJECTIVE To investigate the predictive/prognostic role of VEGF in patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS VEGF plasma levels were measured preoperatively in 1036 patients with UCB who underwent RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The correlation between plasma VEGF levels and pathological and survival outcomes was assessed using logistic regression and Cox regression analyses. Discrimination was assessed using the concordance index (C index). The clinical net benefit was evaluated using decision curve analysis (DCA). RESULTS AND LIMITATIONS Patients with higher pretreatment plasma VEGF levels had poorer recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) according to log-rank tests (all p 0.05). Preoperative plasma VEGF levels were independently associated with RFS, CSS, and OS in preoperative and postoperative multivariable models. However, in all cases the C index increased by

BACKGROUND Posttraumatic stress disorder (PTSD) is associated with autonomic dysfunction as indicated by deficits in the sympathetic and parasympathetic nervous systems. These abnormalities are expressed as elevated heart rate and reduced heart rate variability (HRV), respectively. Intermittent theta-burst stimulation (iTBS), a form of transcranial magnetic stimulation, has demonstrated effectiveness in PTSD. Nevertheless, it remains unclear whether HRV may be an iTBS biomarker for PTSD and whether iTBS impacts autonomic activity. MATERIALS AND METHODS Fifty Veterans with PTSD participated in a randomized controlled trial, receiving ten daily sessions of sham-controlled iTBS (right dorsolateral prefrontal cortex, 1800 pulses/day, 80% active motor threshold, 9.5 min). With a usable dataset of (N = 47), HRV parameters were assessed as predictors of clinical response immediately after stimulation. iTBS effects on autonomic response (mean RR interval, root mean square of successive differences [RMSSD], total power [TP], and low-frequency/high-frequency [LF/HF] ratio) were evaluated using an ultra-short approach. RESULTS TP and RMSSD were significant predictors of acute clinical response to iTBS. Individuals with higher TP had better response to iTBS with improved symptoms on the Clinician-Administered PTSD Scale (rs = -0.58, p = 0.004), and higher functionality on the Social and Occupational Function Scale (rs = 0.43, p = 0.04). Similarly, higher RMSSD was associated with superior outcomes (rs = -0.44, p = 0.04). No other significant changes in HRV metrics were observed (p ≥ 0.05). CONCLUSIONS Our findings indicate that autonomic activity is a potential low-cost and technically simple predictive biomarker of iTBS response in PTSD. Less autonomic dysfunction was associated with superior clinical improvements with iTBS. Future studies might consider HRV acquisition during iTBS, as well as prospective testing of these findings in patients with elevated hyperarousal.

BACKGROUND: Neurodevelopmental impairment is a significant consequence for survivors of surgery for critical congenital heart disease. This study sought to determine if intraoperative methylprednisolone during neonatal cardiac surgery is associated with neurodevelopmental outcomes at 12 months of age and to identify early prognostic variables associated with neurodevelopmental outcomes. METHODS: A planned secondary analysis of a two-center, double-blind, randomized, placebo-controlled trial of intraoperative methylprednisolone in neonates undergoing cardiac surgery was performed. A brain injury biomarker was measured perioperatively. Bayley Scales of Infant and Toddler Development-III (BSID-III) were performed at 12 months of age. Two sample t-tests and generalized linear models were used. RESULTS: There were 129 participants (n=61 methylprednisolone, n=68 placebo). There were no significant differences in BSID-III scores and brain injury biomarker levels between the two treatment groups. Participants who underwent a palliative (vs. corrective) procedure had lower mean BSID-III cognitive (101±15 vs. 106±14, p=0.03) and motor scores (85±18 vs. 94±16, p

Background This study is designed to evaluate the predictive value of derived monocyte to lymphocyte ratio (dMLR), neutrophil to lymphocyte ratio (NLR) and eosinophil to lymphocyte ratio (ELR) for lymph node metastasis (LNM) in gastric signet ring cell carcinoma (SRCC) patients. Methods We carried out a retrospective analysis for 203 eligible patients who underwent radical gastrectomy between January 2011 and September 2020. Results The diagnostic sensitivity and specificity for dMLR were 60.3% and 72.2%, respectively; while for NLR and ELR were 64.1% and 66.6%, and 91.6% and 23.6%, respectively. The dMLR and NLR were identified as independent predictors of LNM, but ELR was not. A nomogram was developed incorporating dMLR and clinical characteristics with AUC of 0.868, and the outcome of DCA supported good clinical benefit. Conclusions dMLR is a promising novel preoperative biomarker to predict LNM of gastric SRCC.

BACKGROUND Atherosclerosis and vascular inflammatory response have been considered as risk factors for non-typhoidal Salmonella (NTS) vascular infection. The study aims to assess the risk of vascular infection by measuring atherosclerosis severity, NTS vascular infection (NTSVI) score, and serum levels of inflammatory markers in people with NTS bacteremia. METHODS A prospective observational study was conducted in two medical centers and two regional hospitals. Adults aged ≥50 years with NTS bacteremia who underwent computed tomography (CT) scan for revealing vascular infections were enrolled. The degree of atherosclerosis was scaled by a calcium score determined by a CT scan. Serum concentrations of inflammatory biomarkers were determined in the patients enrolled in a medical center. RESULTS Fourteen (20.3%) of 69 patients with NTS bacteremia had vascular infections. Calcium scores over the thoracic (12,540 vs. 3,261, P = 0.0005) and abdominal (9755 vs. 3,461, P = 0.0006) aorta of those with vascular infections were higher than those without vascular infection. All vascular infections were present in the high-risk group (NTSVI score ≥1), yielding a sensitivity of 100% and specificity of 30.9%. Among 17 low-risk patients (NTSVI score

Background It is imperative that non-compliance with statins be identified and addressed to maximize their clinical benefits. Patient self-reporting methods are convenient to apply in clinical practice but need to be validated. Objective We studied the concordance of a patient self-report method, Morisky eight-item medication adherence scale (MMAS)), with the pill count method in measuring adherence with statins and their correlation with extended lipid profile parameters and serum hydroxyl-methylglutaryl coenzyme A reductase (HMGCoA-R) enzyme levels. Methods MMAS and the pill count method were used to measure the adherence with statins in patients on statins for any duration. Patients were subjected to an estimation of extended lipid profile and serum HMGCoA-R levels at the end of three months follow-up. Results Out of a total of 200 patients included in the study, 117 patients had a low adherence (score less than 6 on MMAS) whereas 65 and 18 patients had medium (score 6 or 7) and high adherence (score of 8), respectively. The majority of patients who had low adherence to statins by MMAS were nonadherent by the pill count method yielding a concordance of 96.5%. Medium or high adherence to statins by the MMAS method had a concordance of 89.1% with the pill count method. The levels of total cholesterol, low-density lipoprotein-cholesterol, apolipoprotein B, and HMGCoA-R were negatively correlated with compliance measured by pill count and MMAS in a statistically significant way and with similar correlation coefficients. HMGCoA-R levels demonstrated a plateau phenomenon, with levels being 9-10 ng/ml when compliance with statin therapy was greater than 60% by pill count and greater than 6 on the Morisky scale. Conclusion In conclusion, MMAS and the pill count method showed concordance in measuring adherence to statins. These methods need to be explored further for their interchangeability as surrogates for biomarker levels.

Slow-cycling/dormant cancer cells (SCCs) have pivotal roles in driving cancer relapse and drug resistance. A mechanistic explanation for cancer cell dormancy and therapeutic strategies targeting SCCs are necessary to improve patient prognosis, but are limited because of technical challenges to obtaining SCCs. Here, by applying proliferation-sensitive dyes and chemotherapeutics to non-small cell lung cancer (NSCLC) cell lines and patient-derived xenografts, we identified a distinct SCC subpopulation that resembled SCCs in patient tumors. These SCCs displayed major dormancy-like phenotypes and high survival capacity under hostile microenvironments through transcriptional upregulation of regulator of G protein signaling 2 (RGS2). Database analysis revealed RGS2 as a biomarker of retarded proliferation and poor prognosis in NSCLC. We showed that RGS2 caused prolonged translational arrest in SCCs through persistent eukaryotic initiation factor 2 (eIF2α) phosphorylation via proteasome-mediated degradation of activating transcription factor 4 (ATF4). Translational activation through RGS2 antagonism or the use of phosphodiesterase 5 inhibitors, including sildenafil (Viagra), promoted ER stress-induced apoptosis in SCCs in vitro and in vivo under stressed conditions, such as those induced by chemotherapy. Our results suggest that a low-dose chemotherapy and translation-instigating pharmacological intervention in combination is an effective strategy to prevent tumor progression in NSCLC patients after rigorous chemotherapy.

BACKGROUND: In Helicobacter pylori-driven gastric cancer, mucosal colonization induces chronic inflammation that may variably progress to cancer. Prospective studies of circulating inflammation-related proteins have suggested weak associations with gastric cancer risk. To assess potential utility as a screening tool in clinical settings, we examined circulating levels of a wide range of key inflammation molecules for associations with early-stage gastric cancer. METHODS: We used pre-treatment EDTA plasma from 239 individuals with early-stage noncardia gastric cancer (203 stage I and 36 stage II) and 256 age-frequency-matched H. pylori-seropositive cancer-free controls within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Levels of 92 biomarkers were measured by proximity extension assays using Olink’s Proseek Immuno-oncology Panel. Odds ratios (ORs) for association with gastric cancer risk were calculated for quantiles (two to four categories) of each biomarker from unconditional logistic regression models, adjusted for age, sex, smoking and alcohol consumption. Two-sided p-values

Purpose Cardiac myxoma (CM), the most common cardiac tumor in adults, accounts for 50–75% of benign cardiac tumors. The diagnosis of CM is often elusive, especially in young stroke survivors and transthoracic echocardiography (TTE) is the initial technique for the differential diagnostics of CM. Less invasive cardiac computed tomography (CT) and magnetic resonance imaging (MRI) are not available for the majority of cardiac patients. Here, a robust imaging approach, ortho-Positronium (o-Ps) imaging, is presented to determine cardiac myxoma extracted from patients undergoing urgent cardiac surgery due to unexpected atrial masses. We aimed to assess if the o-Ps atom, produced copiously in intramolecular voids during the PET imaging, serves as a biomarker for CM diagnosing. Methods Six perioperative CM and normal (adipose) tissue samples from patients, with primary diagnosis confirmed by the histopathology examination, were examined using positron annihilation lifetime spectroscopy (PALS) and micro-CT. Additionally, cell cultures and confocal microscopy techniques were used to picture cell morphology and origin. Results We observed significant shortening in the mean o-Ps lifetime in tumor with compare to normal tissues: an average value of 1.92(02) ns and 2.72(05) ns for CM and the adipose tissue, respectively. Microscopic differences between tumor samples, confirmed in histopathology examination and micro-CT, did not influenced the major positronium imaging results. Conclusions Our findings, combined with o-Ps lifetime analysis, revealed the novel emerging positronium imaging marker (o-PS) for cardiovascular imaging. This method opens the new perspective to facilitate the quantitative in vivo assessment of intracardiac masses on a molecular (nanoscale) level.

Responsive assessment of disease activity in patients who have rheumatoid arthritis (RA) is necessary to evaluate therapeutic efficacy and guide treatment. We compared the utility of the multibiomarker disease activity (MBDA) score in the assessment of RA disease activity with that of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) score and the Clinical Disease Activity Index (CDAI) in a multicenter, randomized, placebo-controlled trial of repository corticotropin injection (RCI) in patients with persistently active RA.Patients received 80 units of RCI twice weekly during a 12-week open-label period; those who experienced low disease activity at week 12 were randomly assigned to receive either 80 units of RCI or placebo twice weekly during a 12-week double-blind period. Changes in disease activity (measured by DAS28-ESR, CDAI, and MBDA scores) and correlations between MBDA scores and both DAS28-ESR and CDAI scores were assessed.Changes from baseline in DAS28-ESR and CDAI scores suggested that RCI therapy led to clinically meaningful improvements in disease activity, but improvements from baseline in MBDA scores were below the minimally important difference threshold. For the DAS28-ESR and CDAI, correlations with total MBDA and individual component scores were generally low (r ≤ 0.3) and occasionally moderate (r 0.3 but r 0.5).The results of the present study suggest overall MBDA scores are not sufficiently responsive for assessing RA disease activity after RCI therapy. These findings are consistent with those seen with other RA drugs and, although they are from a clinical trial, suggest the MBDA should not be a preferred disease activity measure in clinical practice.

To determine the optimal combination of imaging and biochemical biomarkers for use in the prediction of knee osteoarthritis (OA) progression.The present study was a nested case-control trial from the Foundation of the National Institutes of Health OA Biomarkers Consortium that assessed study participants with a Kellgren/Lawrence grade of 1-3 who had complete biomarker data available (n = 539 to 550). Cases were participants' knees that had radiographic and pain progression between 24 and 48 months compared to baseline. Radiographic progression only was assessed in secondary analyses. Biomarkers (baseline and 24-month changes) that had a P value of0.10 in univariate analysis were selected, including quantitative cartilage thickness and volume on magnetic resonance imaging (MRI), semiquantitative MRI markers, bone shape and area, quantitative meniscal volume, radiographic progression (trabecular bone texture [TBT]), and serum and/or urine biochemical markers. Multivariable logistic regression models were built using 3 different stepwise selection methods (complex models versus parsimonious models).Among baseline biomarkers, the number of locations affected by osteophytes (semiquantitative), quantitative central medial femoral and central lateral femoral cartilage thickness, patellar bone shape, and semiquantitative Hoffa-synovitis predicted OA progression in most models (C statistic 0.641-0.671). In most models, 24-month changes in semiquantitative MRI markers (effusion-synovitis, meniscal morphologic changes, and cartilage damage), quantitative central medial femoral cartilage thickness, quantitative medial tibial cartilage volume, quantitative lateral patellofemoral bone area, horizontal TBT (intercept term), and urine N-telopeptide of type I collagen predicted OA progression (C statistic 0.680-0.724). A different combination of imaging and biochemical biomarkers (baseline and 24-month change) predicted radiographic progression only, which had a higher C statistic of 0.716-0.832.The present study highlights the combination of biomarkers with potential prognostic utility in OA disease-modifying trials. Properly qualified, these biomarkers could be used to enrich future trials with participants likely to experience progression of knee OA.

Aims The exploration of novel immunomodulatory interventions to improve outcome in heart failure (HF) is hampered by the complexity/redundancies of inflammatory pathways, which remain poorly understood. We thus aimed to investigate the associations between the activation of diverse immune processes and outcomes in patients with HF. Methods and results We measured 355 biomarkers in 2022 patients with worsening HF and an independent validation cohort (n = 1691) (BIOSTAT-CHF index and validation cohorts), and classified them according to their functions into biological processes based on the gene ontology classification. Principal component analyses were used to extract weighted scores per process. We investigated the association of these processes with all-cause mortality at 2-year follow-up. The contribution of each biomarker to the weighted score(s) of the processes was used to identify potential therapeutic targets. Mean age was 69 (±12.0) years and 537 (27%) patients were women. We identified 64 unique overrepresented immune-related processes representing 188 of 355 biomarkers. Of these processes, 19 were associated with all-cause mortality (10 positively and 9 negatively). Increased activation of ‘T-cell costimulation’ and ‘response to interferon-gamma/positive regulation of interferon-gamma production’ showed the most consistent positive and negative associations with all-cause mortality, respectively, after external validation. Within T-cell costimulation, inducible costimulator ligand, CD28, CD70, and tumour necrosis factor superfamily member-14 were identified as potential therapeutic targets. Conclusions We demonstrate the divergent protective and harmful effects of different immune processes in HF and suggest novel therapeutic targets. These findings constitute a rich knowledge base for informing future studies of inflammation in HF.

Background: Identifying metastatic melanoma in the sentinel lymph node (SLN) is important because 80% of SLN biopsies are negative and 11% of patients develop complications. The neutrophil-to-lymphocyte ratio (NLR), a biomarker of micrometastatic disease, could improve prediction models for SLN status. We externally validated existing models and developed ‘MelRisk’ prognostic score to better predict SLN metastasis. Methods: The models were externally validated using data from a multicenter cohort study of 1,251 adults. Additionally, we developed and internally validated a new prognostic score `MelRisk’, using candidate predictors derived from the extant literature. Results: The Karakousis model had a C-statistic of 0.58 (95% CI, 0.54–0.62). The Sondak model had a C-statistic of 0.57 (95% CI 0.53–0.61). The MIA model had a C-statistic of 0.60 (95% CI. 0.56–0.64). Our ‘MelRisk’ model (which used Breslow thickness, ulceration, age, anatomical site, and the NLR) showed an adjusted C-statistic of 0.63 (95% CI, 0.56–0.64). Conclusion: Our prediction tool is freely available in the Google Play Store and Apple App Store, and we invite colleagues to externally validate its performance.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

Background Postoperative lymphopenia (PL) after spine surgery is reported to be an indicator of surgical-site infection (SSI). PL without SSI is often encountered, resulting in a treatment dilemma. We focused on PL, so as to improve the accuracy of detecting SSI. Methods In total, 329 patients underwent spine surgery, including nine patients presenting with SSI. The complete blood cell counts, differential counts, and C-reactive protein (CRP) level were measured pre-surgery and on postoperative days 2, 7, and 14. The relationships between PL and SSI were evaluated, and PL and non-PL conditions were compared among all cases. We then divided the patients into two groups: PL and non-PL, and determined the useful serological markers using receiver operating characteristic curves. Results Sixty-one patients presented with PL, including four with SSI. However, PL was not directly suggested as a biomarker of SSI (p = 0.067). We revealed PL as a risk factor for SSI (p = 0.004, Odds ratio: 7.54). Among all cases, the lymphocyte count and CRP level differed significantly between the PL and non-PL groups at all perioperative time-points. The white blood cell count, neutrophil count, and CRP levels on postoperative day 7 significantly differed between the SSI and non-SSI cases in the PL group. The area under the curve (AUC) for CRP was greater than that of the other parameters. The neutrophil count was only effective as a marker in the non-PL group. The combination of two cutoff values (CRP: 3.7 mg/dL (PL group) and neutrophil count: 6172/μL (non-PL group)) presented high specificity (87.2%) and sensitivity (88.9%), while only one cutoff value (CRP: 2.9 mg/dL) had a specificity of 77.4% and sensitivity of 77.8%. Conclusions Approximately one-fifth of patients developed PL post-surgery, which was a risk factor for SSI, with constant high inflammation. Grouping based on PL and establishing diagnostic cutoff values are more appropriate than establishing only one cutoff value for overall cases.

BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

Research question Whether extracellular vesicle-derived lncRNAs could serve as promising circulating biomarkers for endometriosis? Design To obtain novel diagnostic markers, we enrolled 85 patients with endometriosis as the endometriosis group and 86 unaffected participants as the control group. RNA sequencing was performed to identify exosomal long non-coding RNAs (lncRNAs) that are differentially expressed between women with endometriosis (n=5) and unaffected participants (n=6). Messenger RNA and lncRNA sequences of the plasma exosomes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. LncRNA expression levels were further validated using quantitative reverse transcriptase polymerase chain reaction. Moreover, receiver operating characteristic curve analysis was performed to determine the diagnostic value of candidate lncRNAs. Clinical features were correlated to the expression levels of candidate lncRNAs. Results We found that 210 lncRNAs were significantly dysregulated; among these, expression of LINC01569, RP3-399L15.2, FAM138B, and CH507-513H4.6 was significantly decreased, whereas expression of RP11-326N17.2, KLHL7-AS1, and MIR548XHG was increased, in the plasma of patients with endometriosis. Combined expression level of RP3-399L15.2 and CH507-513H4.6 was used to distinguish patients with endometriosis from control participants; the results revealed a sensitivity of 80.00% and specificity of 85.45% at the cutoff point, and an area under the ROC curve of 0.9045. Our findings demonstrated the potential of these two lncRNAs as diagnostic biomarkers for endometriosis. Moreover, CH507-513H4.6 alone may be useful to detect early-stage endometriosis lesions. Conclusions The combination of RP3-399L15.2 and CH507-513H4.6 can be potential candidates for endometriosis biomarkers.

Active lesions in the small bowel (SB) have been independently associated with poorer prognoses in patients with Crohn's disease (CD)1; however, there has been a lack of accurate and convenient screening methods. Past studies have found that serum levels of the glycoprotein leucine-rich α2 glycoprotein (LRG) correlates with endoscopic activity in ulcerative colitis,2,3 and this is now available for routine clinical use as a biomarker in patients with inflammatory bowel disease in Japan. LRG has not yet been thoroughly verified in CD, and we investigated whether it can be used as a serum biomarker for detecting SB mucosal activity in patients with CD.

Objectives Current treatments are effective only in 30% of lupus nephritis patients emphasizing the need for novel therapeutic strategies. To develop mechanistic hypotheses and explore novel biomarkers, we analyzed the longitudinal urinary proteomic profiles in patients with lupus nephritis undergoing treatment. Methods We quantified 1,000 urinary proteins in 30 patients with lupus nephritis at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single cell transcriptomics of renal biopsies from lupus nephritis patients. Results Our analysis revealed multiple biological pathways including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization that could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with lupus nephritis as compared to controls without SLE. IL-16, CD163, and TGF-β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction of urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in lupus nephritis kidneys. IL-16 producing cells were found at key sites of kidney injury. Conclusion Urine proteomics may profoundly change the diagnosis and management of lupus nephritis by noninvasively monitor active intrarenal biological pathways. These findings implicate IL-16 in lupus nephritis pathogenesis designating it as a potentially treatable target and biomarker.

Background: Periprocedural myocardial injury (PMI) is a frequent complication of percutaneous coronary intervention (PCI) associated with poor prognosis. However, no effective method has been found to identify patients at risk of PMI before the procedure. MicroRNA-133a (miR-133a) has been reported as a novel biomarker in various cardiovascular diseases. Herein, it was sought to determine whether circulating miR-133a could predict PMI before the procedure. Methods: Eighty patients with negative preoperative values of cardiac troponin T (cTnT) receiving elective PCI for stable coronary artery disease (CAD) were recruited. Venous serum samples were collected on admission and within 16–24 hours post-PCI for miRNA measurements. PMI was defined as a cTnT value above the 99% upper reference limit (URL) after the procedure. The association between miR-133a and PMI was further assessed. Results: Periprocedural myocardial injury occurred in 48 patients. The circulating level of miR-133a was significantly higher in patients with PMI before and after the procedure (both p < 0.001). Receiver operating characteristic curve analysis of the preoperative miR-133a level revealed an area under the curve (AUC) of 0.891, with a sensitivity of 93.8% and a specificity of 71.9% to predict PMI. Additionally, a decrease was found in fibroblast growth factor receptor 1 (FGFR1) in parallel with an increase in miR-133a levels in patients with PMI. Conclusions: This study demonstrates for the first time that serum miR-133a can be used as a novel biomarker for early identification of stable CAD patients at risk of PMI undergoing elective PCI. The miR-133a-FGFR1 axis may be involved in the pathogenesis of PMI.

Early tumor size reduction (TSR) has been explored as a prognostic factor for survival in patients with advanced melanoma in clinical trials. The purpose of this analysis is to validate, in a routine clinical milieu, the predictive capacity of TSR by 10% for overall survival (OS) and progression-free survival (PFS) and to compare its predictive performance with the RECIST 1.1 criteria.This retrospective study was approved by the local ethics committee. A total of 152 patients with both CT before immunotherapy initiation and at first response evaluation after immunotherapy initiation were included. Prior to statistical analysis, treatment response was trichotomized as follows: Complete response and/or partial response, stable disease and progressive disease. Furthermore, response was dichotomized regarding TSR (TSR ≥ 10% and TSR10%). Kaplan-Meier survival estimates, Cox regression and Harrel's concordance index (C-index) were computed for prediction of overall survival and progression-free survival.Tumor size reduction by at least 10% significantly differentiated between patients with increased survival from the ones with decreased survival (median OS: TSR ≥ 10%: 2137 days vs. TSR10%: 263 days) (p0.001) (median PFS: TSR ≥ 10%: 590 days vs. TSR10%: 11 days) (p0.001). RECIST 1.1. criteria had a slightly higher C-index for overall survival reflecting a slight superior predictive capacity (RECIST: 0.69 vs TSR: 0.64) but a similar predictive capacity regarding progression-free survival (both: 0. 63).Early tumor size reduction serves as a simple-to-use metric which can be implemented on the first follow-up CT. Tumor size reduction by at least 10% can be considered an additional biomarker predictive of overall survival and progression-free survival in routine clinical care and not only in the context of clinical trials in patients with advanced melanoma undergoing immunotherapy. Nevertheless, RECIST-based criteria should remain the main tool of treatment response assessment until results of prospective studies validating the TSR method are available.

BACKGROUND/PURPOSE Klebsiella pneumoniae bacteremia-induced sepsis is a clinically important condition with a high mortality rate and various known virulence factors. However, studies on the association of these virulence factors with the occurrence of K. pneumoniae bacteremia-induced sepsis are scarce. We aimed to investigate clinical variables and virulence factors in patients with K. pneumoniae bacteremia-induced sepsis. METHODS We retrospectively reviewed the medical records of 76 patients with K. pneumoniae bacteremia between January 2012 and July 2017. Patients were divided into sepsis (n = 25) and non-sepsis (n = 51) groups. Patient background characteristics, antimicrobial regimens, and prognosis were evaluated. We assessed the distribution of virulence factors related to K. pneumoniae, such as mucoviscosity, capsular polysaccharide, and siderophores. Siderophore production levels were determined by measuring the orange halo zone on chrome azurol S agar plate assay. RESULTS There were no intergroup differences in male-to-female ratio and age. Multivariable analysis revealed that siderophore production level (p

Bipolar androgen therapy (BAT) is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively identified patients with mCRPC that achieved deep PSA responses to BAT. All patients with available next-generation molecular sequencing harbored pathogenic mutations in TP53 and/or a homologous recombination DNA repair gene. BACKGROUND: Bipolar androgen therapy (BAT) is an emerging treatment strategy for men with metastatic castration resistant prostate cancer (mCRPC) whereby serum testosterone is cycled from supraphysiologic to near-castrate levels each month. BAT has been shown to induce clinical responses in a significant proportion of patients, some of which are extreme. We explored the clinical and molecular characteristics of patients with mCRPC who achieved deep responses to BAT. METHODS: We conducted a retrospective analysis of patients with mCRPC treated with BAT at Johns Hopkins. We identified 22 of 114 (19%) patients with mCRPC who achieved ≥70% PSA reductions upon treatment with BAT. All patients were treated using 400 mg testosterone cypionate intramuscularly every 28 days, together with continuous LHRH agonist therapy. Clinical-grade DNA sequencing was obtained using commercially available assays. RESULTS: Somatic next-generation sequencing was obtained for 15 of 22 (68%) patients. Of these 15 extreme PSA responders with sequencing data available, All 15 of 15 (100%) harbored a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene. Among the subset of patients with measureable disease (N = 15), 10 patients (67%) achieved an objective response including one patient with a complete response. The median radiographic progression-free survival of these deep PSA responders was 11.3 months (95% CI, 7.9–25.0 months). CONCLUSIONS: We observed an enrichment of TP53 and HRD mutations in mCRPC patients with extreme PSA responses to BAT, with durability lasting about a year. These data support the hypothesis that BAT may most benefit patients with DNA repair-deficient mCRPC. Further studies of BAT in biomarker-selected mCRPC populations (ie, TP53/HRD-mutated) are warranted.

Aims: Given the reversibility of methylation, biomarkers with discriminating ability are of great interest for targeted therapeutic sites. Materials & methods: Methylation array data of 461 lung adenocarcinoma (LUAD) patients comprising of 458 tumor and 32 LUAD paracancerous samples were compared using partial least squares discrimination analysis and receiver operating characteristics analysis. Results: A six-DNA methylation signature (corresponding to five genes) was found to significantly discriminate normal and LUAD samples. Kyoto Encyclopedia of Genes and Genomes analysis indicated enrichment of methylation sites in the Wnt pathway in LUAD compared with controls. Conclusion: This six-DNA methylation signature demonstrated potential as a novel biomarker for diagnosis and therapeutic targets. Further, inhibition of Wnt signaling pathway may be an important step in LUAD progression.

Background Inappropriate and excessive activation of type I interferon (IFN) system is a key feature of systemic lupus erythematosus (SLE), and its targeting has led to important achievements in the development of novel drugs for SLE. Aim of the work To evaluate the serum levels of interferon lambda IFNλ3 (IL28B) in Egyptian patients with SLE and investigate its potential relation with different clinical and laboratory parameters. Patients and methods The study included 40 SLE patients and 40 controls. The SLE disease activity index (SLEDAI) was assessed. The measurement of serum levels of IFNλ3 was performed in all participants using enzyme linked immunosorbent assay (ELISA). Results The mean age of the patients was 26.8 ± 7.8 years with disease duration 5.1 ± 4.5 years and they were 35 females and 5 males. The serum levels of IFNλ3 were significantly higher in SLE patients (9.7 ± 12.47 pg/mL) compared to the control (5.13 ± 1.63 pg/mL)(p = 0.02). Significant correlations were observed between serum IFNλ3 and serositis (r = 0.35,p = 0.03), C3 consumption (r −0.33, p = 0.04) and SLEDAI (r 0.34, p = 0.03). On multivariate regression analysis, serositis and SLEDAI (but not C3) were significant independent predictors of IFNλ3 levels (β = 0.08, p = 0.037 and β = 0.06, p = 0.014 respectively). Conclusion The results support a possible role of IFNλ3/IL28B in the immunopathogenesis of SLE. The significant association of serum IFNλ3 with disease activity highlights the utility of IFNλ3 as a novel biomarker for monitoring disease activity and predicting severity in SLE. Further studies on IFNλ3 in SLE could be promising in the development of personalized therapy for lupus patients.

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.

As the most common cause of dementia, the study of Alzheimer’s disease (AD) faces challenges in terms of understanding the cause, monitoring the pathogenesis, and developing early diagnosis and effective treatment. Rapid and accurate identification of AD biomarkers in the brain is critical to provide key insights into AD and facilitate the development of early diagnosis methods. In this work, we developed a platform that enables a rapid screening of AD biomarkers by employing graphene-assisted Raman spectroscopy and machine learning interpretation in AD transgenic animal brains. Specifically, we collected Raman spectra on slices of mouse brains with and without AD and used machine learning to classify AD and non-AD spectra. By contacting monolayer graphene with the brain slices, the accuracy was significantly increased from 77% to 98% in machine learning classification. Further, using linear supporting vector machine (SVM), we identified a spectral feature importance map that reveals the importance of each Raman wavenumber in classifying AD and non-AD spectra. Based on this spectral feature importance map, we identified AD biomarkers including Aβ and tau proteins, and other potential biomarkers, such as triolein, phosphatidylcholine, and actin, which have been confirmed by other biochemical studies. Our Raman-machine learning integrated method with interpretability is promising to greatly accelerate the study of AD and can be extended to other tissues, biofluids, and for various other diseases.

Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.

We systemically identified tuberculosis (TB)-related DNA methylation biomarkers and further constructed classifiers for TB diagnosis. TB-related DNA methylation datasets were searched through October 3, 2020. Limma and DMRcate were employed to identify differentially methylated probes (DMPs) and regions (DMRs). Machine learning methods were used to construct classifiers. The performance of the classifiers was evaluated in discovery datasets and a prospective independent cohort. Eighty-nine DMPs and 24 DMRs were identified based on 67 TB patients and 45 healthy controls from 4 datasets. Nine and three DMRs were selected by elastic net regression and logistic regression, respectively. Among the selected DMRs, two regions (chr3: 195635643–195636243 and chr6: 29691631–29692475) were differentially methylated in the independent cohort (p = 4.19 × 10−5 and 0.024, respectively). Among the ten classifiers, the 3-DMR logistic regression classifier exhibited the strongest performance. The sensitivity, specificity, and area under the curve were, respectively, 79.1%, 84.4%, and 0.888 in the discovery datasets and 64.5%, 90.3%, and 0.838 in the independent cohort. The differential diagnostic ability of this classifier was also assessed. Collectively, these data showed that DNA methylation might be a promising TB diagnostic biomarker. The 3-DMR logistic regression classifier is a potential clinical tool for TB diagnosis, and further validation is needed., Graphical abstract, We systemically identified TB-related DNA methylation biomarkers and constructed diagnostic classifiers. A 3-DMR logistic regression classifier showed excellent performance in discovery datasets and a prospective cohort. DNA methylation might be a promising TB-related biomarker and the 3-DMR logistic regression classifier is a potential clinical tool for TB diagnosis.

Background Many prognostic models for Hepatocellular Carcinoma (HCC) have been developed to inform patients and doctors about individual prognosis. Previous reviews of these models were qualitative and did not assess performance at external validation. We assessed the performance of prognostic models for HCC and set a benchmark for biomarker studies. Methods All externally validated models predicting survival for patients with resected HCC were systematically reviewed. After selection, we extracted descriptive statistics and aggregated c-indices using meta-analysis. Results Thirty-eight validated prognostic models were included. Models used on average 7 (IQR:4–9) prognostic factors. Tumor size, tumor number, and vascular invasion were almost always included. Alpha-fetoprotein (AFP) was commonly incorporated since 2007. Recently, the more subjective items ascites and encephalopathy have been dropped. Eight established models performed poor to moderate at external validation, with a pooled C-index below 0.7; including the Barcelona Clinic Liver Cancer (BCLC) system, the American Joint Committee on Cancer (AJCC) 7th edition, the Cancer of the Liver Italian (CLIP) Program, and the Japan Integrated Staging (JIS) score. Out of 24 prognostic models predicting OS, only 6 (25%) had good performance at external validation with pooled C-indices above 0.7; the Li-post (0.77), Li-OS (0.74), Yang-pre (0.74), Yang-post (0.76), Shanghai-score (0.70), and Wang-nomogram (0.71). Models improved over time, but overall performance and study quality remained low. Conclusions Six validated prognostic models demonstrated good performance for predicting survival after resection of HCC. These models can guide patients and doctors and are a benchmark for future models incorporating novel biomarkers.

Background Non-invasive clinical algorithms for the detection of liver fibrosis (LF) can reduce the need for liver biopsy (LB). We explored the implementation of two serum biomarkers, enhanced liver fibrosis (ELF) and Mac-2 binding protein glycosylation isomer (M2BPGi), in clinical algorithms for LF in chronic hepatitis B (CHB) patients. Methods Two clinical algorithms were applied to 152 CHB patients: (1) transient elastography (TE) followed by biomarkers (TE/ELF and TE/M2GPGi); (2) biomarker test followed by TE (ELF/TE and M2BPGi/TE). Using the cut-off value or index for the detection of advanced LF (TE≥F3; 9.8 in ELF and 3.0 in M2BPGi), LB was expected to be performed in cases with discordant TE and biomarker results. Results In both algorithms, the expected number of LBs was lower when using M2BPGi than when using ELF (TE/ELF or ELF/TE, 13.2% [N=20]; TE/M2BPGi or M2BPGi/TE, 9.9% [N=15]), although there was no statistical difference (P=0.398). In the TE low-risk group (TE≤F2), the discordance rate was significantly lower in the TE/M2BPGi approach than in the TE/ELF approach (1.5% [2/136] vs. 11.0% [15/136], P=0.002). In the biomarker low-risk group, there was no significant difference between the ELF/TE and M2BPGi/TE approaches (3.9% [5/126] vs. 8.8% [13/147], P=0.118). Conclusions Both ELF and M2BPGi can be implemented in non-invasive clinical algorithms for assessing LF in CHB patients. Given the lowest possibility of losing advanced LF cases in the low-risk group when using the TE/M2BPGi approach, this combination seems useful in clinical practice.

Considerable advancements have been made in the quantification of biofluid-based biomarkers for traumatic brain injury (TBI), which provide a clinically accessible window to investigate disease mechanisms and progression. Methods with improved analytical sensitivity compared with standard immunoassays are increasingly used, and blood tests are being used in the diagnosis, monitoring, and outcome prediction of TBI. Most work to date has focused on acute TBI diagnostics, while the literature on biomarkers for long-term sequelae is relatively scarce. In this review, we give an update on the latest developments in biofluid-based biomarker research in TBI and discuss how acute and prolonged biomarker changes can be used to detect and quantify brain injury and predict clinical outcome and neuropsychiatric sequelae.

Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability.All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients.The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P.001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve,0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices.The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.

Background Urine tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) (NephroCheck, Ortho Clinical Diagnostics, Raritan, NJ, USA) is a US Food and Drug Administration-approved biomarker for risk assessment of acute kidney injury (AKI) in critically ill adult patients in intensive care units; however, its clinical impact in the emergency department (ED) remains unproven. We evaluated the utility of NephroCheck for predicting AKI development and short-term mortality in the ED. Methods This was a prospective, observational, five-center international study. We consecutively enrolled ED patients admitted with ≥30% risk of AKI development (assessed by ED physician: ED score) or acute diseases. Serum creatinine was tested on ED arrival (T0), day 1, and day 2 (T48); urine for NephroCheck was collected at T0 and T48. We performed ROC curve and reclassification analyses. Results Among the 529 patients enrolled (213 females; median age, 65 years), AKI developed in 59 (11.2%) patients. The T0 NephroCheck value was higher in the AKI group than in the non-AKI group (median 0.77 vs. 0.29 (ng/m)2/1,000, P=0.001), and better predicted AKI development than the ED score (area under the curve [AUC], 0.64 vs. 0.53; P=0.04). In reclassification analyses, adding NephroCheck to the ED score improved the prediction of AKI development (P Conclusions NephroCheck can predict both AKI development and short-term mortality in at-risk ED patients. NephroCheck would be a useful biomarker for early ruling-in or ruling-out of AKI in the ED.

BACKGROUND: Interest in therapeutic applications of exogenous ketones has grown significantly, spanning patients with heart failure to endurance athletes. Exogenous ketones engender significant effects on cardiac function in heart failure and provide an ergogenic benefit in athletes. The aim of this study was to assess the effects of exogenous ketones on cardiac function in healthy participants. METHODS: In a single-arm intervention study, 20 fasting, healthy participants underwent comprehensive echocardiography (two-dimensional, Doppler, and strain) before and 30 min after weight-based oral ketone ester administration. The relationship between changes in log-transformed biomarker levels and change in absolute global longitudinal strain (GLS) was assessed using linear regression. RESULTS: The mean age was 30 ± 7 years, 50% were women, 45% were nonwhite, and the average body mass index was 24.3 ± 3.1 kg/m(2). Ketone ingestion acutely elevated β-hydroxybutyrate levels from a median of 0.13 mmol/L (interquartile range, 0.10–0.37 mmol/L) to 3.23 mmol/L (interquartile range, 2.40–4.97 mmol/L) (P < .001). After ketone ester consumption, systolic blood pressure, heart rate, biventricular function, left ventricular GLS, and left atrial (LA) strain all augmented, while systemic vascular resistance decreased. Displayed as mean change, increases in ejection fraction (3.1%; 95% CI, 2.0%−4.2%; P < .001), GLS (2.0%; 95% CI, 1.4%−2.7%; P < .001), right ventricular S′ (1.1 cm/sec; 95% CI, 0.4–1.8 cm/sec; P = .004), LA reservoir strain (7%; 95% CI, 3%−12%; P = .005), and LA contractile strain (4%; 2%−6%; P = .001) were observed. During robustly achieved ketosis, change in GLS was inversely associated with change in nonesterified fatty acids (P = .019). CONCLUSIONS: In a single-arm study, systolic blood pressure, heart rate, biventricular function, and LV and LA strain acutely augmented after ketone ester ingestion in healthy, fasting participants, similar to several effects observed in the failing heart. These data may provide supporting data for the ergogenic benefits observed in athletes and may become increasingly relevant with exogenous ketone consumption across a variety of cardiovascular and noncardiovascular applications.

Aim: This study aimed to access the efficacy of plasma small nucleolar RNAs in early diagnosis of non-small-cell lung cancer (NSCLC). Methods: SNORD83A was selected based on databases and further verified in 48 paired formalin-fixed, paraffin-embedded tissues, as well as in plasma from 150 NSCLC patients and 150 healthy donors. The diagnostic efficiency of plasma SNORD83A, as well as in combination with carcinoembryonic antigen, was determined by receiver operating characteristic analysis. Results: SNORD83A was significantly increased not only in tissues but also in plasma from NSCLC patients compared with those from healthy donors. Plasma SNORD83A was able to act as a diagnostic biomarker for NSCLC. The diagnostic efficiency of carcinoembryonic antigen was also significantly elevated for early-stage NSCLC when combined with SNORD83A. Conclusion: SNORD83A can serve as a diagnostic biomarker for NSCLC.

Objectives: Fetal growth restriction is associated with chronic fetal hypoxia, poor perinatal outcome and increased perinatal mortality. There are no reliable methods to detect cell damage in the central nervous system (CNS) in these patients. The findings of increased an acidic calcium-binding protein (S100B) concentration in biological fluids of infants after brain injury have supported the use of S100B as a biochemical marker of CNS damage. The purpose of the study was to assess blood S100B concentrations in small for gestational age (SGA) and appropriate for gestational age (AGA) newborns and to evaluate the usefulness of S100B for early detection of hypoxia. Material and methods: The investigation was carried out between November 2011 and April 2014. Serum S100B protein level was assessed in cord blood collected from newborns after birth. Medical records of mothers of neonates studied were reviewed for pregnancy induced hypertension (PIH), preeclampsia, maternal smoking during pregnancy and abnormalities in umbilical artery (UA) Doppler ultrasound examination. Results: The study was carried out in 88 SGA neonates and 80 AGA neonates. The median value of S100B protein concentration in the SGA study group was significantly higher than in AGA controls (p < 0.001). Cord blood serum S100B concentration in SGA neonates with prenatal normal UA Doppler ultrasound findings (n = 32) did not differ from that SGA neonates with abnormal prenatal UA Doppler findings (n = 25) (p = 0.74), but was significantly higher than in AGA newborns (p < 0.001). Conclusions : Elevated S100B protein levels in cord blood collected from SGA newborns may be helpful in detecting infants at higher risk of postnatal neurologic disturbances at an early stage.