Inflammatory Biomarkers Research Articles

Abstract PO5-23-11: Elevated linoleic acid levels in red blood cells membrane predicts response to neoadjuvant chemotherapy in breast cancer patients

Abstract Introduction: Fatty acids (FA) consumed in the diet have been implicated in increasing the risk of breast cancer (BC). Humans have a wide variety of FAs, including saturated (SFA), monounsaturated (MUFA), and polyunsaturated (PUFA) FAs. PUFAs can be further classified into omega-3 (n-3) and omega-6 (n-6) PUFAs. While n-3 has been associated with reducing inflammation and promoting apoptosis in BC cells, n-6 has been linked to increased inflammation, oxidative stress, and the promotion of BC cell proliferation and treatment resistance. In healthy women, the n-3 content in mammary tissue correlates with n-3 content in red blood cells (RBCs). The FA profile of the RBC membrane provides an unbiased option to assess lipid intake and composition, reflecting long-term FA intake and providing an objective and sensitive measure of lipid intake and body fat deposits. Notably, BC patients have been found to display a high n-6:n-3 ratio in RBCs, which is associated with inflammatory and oxidative stress biomarkers. The neoadjuvant chemotherapy treatment (NACT) model presents a unique opportunity to study resistance mechanisms in non-metastatic BC patients. In this approach, the absence of tumor (pathologic complete response: pCR, or Residual Cancer Burden (RCB) = 0) after NACT indicates treatment sensitivity and better overall survival (OS). Objective: The objective of this study is to determine whether differences in FA profiles determined in the RBC membrane and plasma are associated with the response to NACT in non-metastatic BC patients. Methods: A prospective study was conducted, including non-metastatic BC patients scheduled to receive NACT. Blood samples were collected before the first cycle of NACT to measure plasma and RBC FA derivatives, SFAs, MUFAs, and PUFAs. The pathological complete response (pCR) and residual cancer burden (RCB) were assessed. Results: A total of twenty-eight BC patients were included in the study. When comparing pCR vs. no-pCR using total SFA, MUFA, and PUFA plasma samples, no significant differences were observed. However, in RBC, an increase in PUFA was associated with a higher rate of no-pCR (**p< 0.01). Furthermore, comparing omega-6 and omega-3 (both PUFA) levels, an increase in omega-6 was associated with no-pCR (**p< 0.01), while no significant differences were observed with omega-3. No differences were obtained in plasma samples for either omega-6 and omega-3. To determine which specific omega-6 PUFAs were responsible for the association with no-pCR, elevated levels of linoleic acid (LA) in RBC were found to be associated with no-pCR (**p< 0.01). Other omega-6 PUFAs, including gamma-linolenic acid (GLA), eicosadienoic acid (EDA), dihomo-gamma linolenic acid (DGLA), and arachidonic acid (ARA), showed no significant associations. Multivariate and regression analysis confirmed LA (C18:2 n-6, LA) as the most relevant FA when assessing RCB (0-1 vs. 2-3) in RBC membranes, but not in plasma. The receiver operating characteristic (ROC) curve analyzing LA levels in RBC showed an area under the curve (AUC) of 0.855 for RCB (sensitivity: 76.9%, specificity: 92.3%). Conclusions: To the best of our knowledge, this is the first study demonstrating a clear connection between RBC membrane FA composition, specifically LA concentration, and the pathological response in BC patients after NACT. The measurements taken in plasma did not show significant associations, suggesting that RBC membrane FA profile of could serve as a relevant prognostic biomarker for studying resistance mechanisms to NACT in early BC patients Table. Measured FAs in RBC membrane and plasma by pathologic complete response *Indicates p<0.05; abbreviations: pCR: pathological complete response; SD: standard deviation; yr: years; BMI: body mass index; HR: hormone receptor; HER2: human epidermal growth factor receptor type-2; NLR: neutrophil to lymphocyte ratio; HG: histological grade; RCB: residual cancer burden; NA: not applicable Citation Format: Benjamin Walbaum, César Sánchez, Francisco Acevedo. Elevated linoleic acid levels in red blood cells membrane predicts response to neoadjuvant chemotherapy in breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-23-11.

Inflammation, Immunonutritive, and Cardiovascular Risk Biomarkers in Men With Alcohol Use Disorder

Inflammation, Immunonutritive, and Cardiovascular Risk Biomarkers in Men With Alcohol Use Disorder

Abstract PO5-13-08: Impact of systemic inflammation markers in response to neoadjuvant pembrolizumab and chemotherapy in triple-negative breast cancer - a retrospective analysis

Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for triple-negative breast cancer (TNBC). Systemic inflammation has been linked to cancer development and overall poor outcomes. Routine blood parameters have been investigated as potential inflammatory biomarkers in patients (pts) with various types of cancer, such as the derived NLR (neutrophils/(leucocytes-neutrophils) ratio (dNLR). A high dNLR has been associated with worse survival in several types of cancer. Specifically, it has been linked to lower pathologic complete response (pCR) rates after neoadjuvant chemotherapy (CTx). We investigated the association between systemic inflammation markers (dNLR, LIPI score and platelet-to-lymphocyte ratio [PLR]) and pCR in early TNBC pts treated with CTx + pembrolizumab (Pemb). Methods: Retrospective analysis of pts with early TNBC treated with Pemb + CTx from April 2022 to March 2023. dNLR was estimated from analytical values of peripheral blood collected before treatment (baseline). dNLR was calculated as the ratio of the absolute neutrophil number to the difference between absolute total leukocyte and absolute neutrophil counts. Univariate and multivariate logistic regression analyses were used to explore the association of dNLR with main clinical characteristics and dNLR capability (distributed as a continuous variable, using median cut-off) to predict pCR. Results: The study included 86 TNBC pts with a median age of 51 years (IQR: 42.2 – 56-7). Most pts had stage II disease (64%) and presented grade 3 tumours (n=66; 78.5%). HER2 low tumours represented 27% (n=23) of the cohort. Germline mutations were present in 20 pts (23%) with the following distribution: BRCA1 (n=14), BRCA 2 (n=5) and PALB2 (n=1). The median stromal tumor infiltrating lymphocytes (TILs) was 20% (IQR: 10-30%). The median Ki67 was 70% (IQR:50%-80%). All pts received Pemb. The majority of pts received carboplatin plus paclitaxel, followed by EC90 (n=77 (90%), while 10% (n=9) did not receive anthracyclines. Data concerning surgical outcomes was available in 80 pts. Pathological complete response rate was 61.2% (n=49). Pts achieving pCR presented significantly higher TILs (p< 0.01). Residual cancer burden (RCB) class (n=80) was distributed as follows: 0: 61% (n=49); I: 13% (n=10); II: 20% (n=16); III: 1% (n=1) and non-assigned: 5% (n=4). In pts with germline mutations (n=20), the pCR rate was 85% (n=17). Median dNLR at baseline was 1.30 (interquartile range (IQR): 0.99 – 1.86). High baseline dNLR levels considered a continuous variable was associated with a higher likelihood of achieving a pCR in univariate (OR: 2.59; 95% CI: 1.01–6.6; p-value = 0.046) but not in multivariate (OR: 2.33; 95%; CI: 0.85–6.33; p-value = 0.097) logistic regression analysis (adjusted for stage and histologic grade). High baseline dNLR, defined by the median cut-off, was associated with an increased likelihood of achieving pCR in both univariate (OR: 3.85; 95% CI: 1.47–10.1; p-value = 0.006) and multivariate (OR: 3.72; 95% CI: 1.28–10.8; p-value = 0.016) logistic regression analysis (adjusted for stage and histologic grade). Conclusion: In this real-life cohort of early TNBC pts treated with Pemb and CTx we found similar pCR rates (61.2%) to the ones reported in the KN522 trial. No association between PLR or LIPI score with pCR was evidenced. High baseline dNLR (assessed as a continuous variable or by the median cut-off) was associated with a higher likelihood of pCR in the univariate analysis. In the multivariate analysis, only high baseline dNLR defined by the median cut-off retained an association with pCR after stage and histologic grade adjustment. Despite several limitations, these exploratory data provide initial evidence of a potential association between dNLR values and independent prediction of pCR. Further research to assess the role of dNLR as a predictive marker for pCR in early TNBC pts treated with CTx + immunotherapy is needed. Citation Format: Martina Spotti, Elie Rassy, Alessandro Viansone, Fiona Pham, Layal Rached, Barbara Pistilli, Charles-Antoine Dutertre, Joana Mourato Ribeiro. Impact of systemic inflammation markers in response to neoadjuvant pembrolizumab and chemotherapy in triple-negative breast cancer - a retrospective analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-08.

New perspectives in the differential diagnosis of jaw lesions: Machine learning and inflammatory biomarkers

This study aimed to assess the diagnostic performance of a machine learning approach that utilized radiomic features extracted from Cone Beam Computer Tomography (CBCT) images and inflammatory biomarkers for distinguishing between Dentigerous Cysts (DCs), Odontogenic Keratocysts (OKCs), and Unicystic Ameloblastomas (UAs). This retrospective study involves 103 patients who underwent jaw lesion surgery in the Maxillofacial Surgery Unit of Federico II University Of Naples between January 2018 and January 2023. Nonparametric Wilcoxon-Mann-Whitney and Kruskal Wallis tests were used for continuous variables. Linear and non-logistic regression models (LRM and NLRM) were employed, along with machine learning techniques such as decision tree (DT), k-nearest neighbor (KNN), and support vector machine (SVM), to predict the outcomes. When individual inflammatory biomarkers were considered alone, their ability to differentiate between OKCs, UAs, and DCs was below 50 % accuracy. However, a linear regression model combining four inflammatory biomarkers achieved an accuracy of 95 % and an AUC of 0.96. The accuracy of single radiomics predictors was lower than that of inflammatory biomarkers, with an AUC of 0.83. The Fine Tree model, utilizing NLR, SII, and one radiomic feature, achieved an accuracy of 94.3 % (AUC = 0.95) on the training and testing sets, and a validation set accuracy of 100 %. The Fine Tree model demonstrated the capability to discriminate between OKCs, UAs, and DCs. However, the LRM utilizing four inflammatory biomarkers proved to be the most effective algorithm for distinguishing between OKCs, UAs, and DCs.

The Biomarkers Associated with Unstable Angina Pectoris (UAP)

Objectives: Coronary artery disease (CAD) is the most common form of CVD that begins as stable angina pectoris (SAP) followed by unstable angina pectoris (UAP) and finally critical stage myocardial infarction (MI), which results from rupture of atherosclerotic plaque and a thrombus that blocks the coronary artery supplying the heart, resulted from the death of part of the heart muscle. The underlying cause of coronary artery disease (CAD) is atherosclerosis, which results from the formation of layers of fatty deposits on the inner walls of the arteries. Early diagnosis of MI has an important role in assisting clinicians in prompt planning for its treatment and thus reducing the number of its deaths. Methods: The present study included 20 UAP patients and 20 healthy individuals (controls). In all the cases and controls, levels of cardiac and inflammatory biomarkers were measured by special kits from Hotgen Company via phosphorous technology using UPT-3A converting phosphor immunological analyzer. Results: The levels of both cardiac and inflammatory biomarkers were significantly increased in UAP cases as compared to controls. Also, there was significant positive correlation between cardiac and inflammatory biomarkers in UAP cases. Conclusions: The positive correlation between most cardiac and inflammatory biomarkers in UAP indicates that inflammation occurs in UAP. Hence it is concluded that inflammatory biomarkers (CRP, Hs-CRP and PCT) and cardiac biomarker (cTnI, H-FABP, CK-MB, NT-proBNP and D-dimer) can be markers of UAP and can be used for diagnostic purposes in patients.

No Effect of High-Eating Frequency Compared with Low-Eating Frequency on Appetite and Inflammation Biomarkers: Results from a Randomized Crossover Clinical Trial

BackgroundEating frequency (EF) focuses on the total number of eating occasions per day and may influence metabolic health. ObjectivesWe sought to examine the effect of high compared with low-EF on appetite regulation and inflammatory biomarkers among healthy adults. MethodsData are from a randomized, crossover trial (the Frequency of Eating and Satiety Hormones study). Participants (n = 50) completed 2 isocaloric 21-d study periods of low EF (3 eating occasions/d) and high EF (6 eating occasions/d) in random order with a 14-d washout period in between. Participants were free-living and consumed their own food, using study-directed, structured meal plans with identical foods and total energy in both study periods. On days 1 and 21 of each EF period, fasting blood was collected during in-person clinic visits to assess plasma concentrations of ghrelin, leptin, adiponectin, and high-sensitivity C-reactive protein (hs-CRP). Linear mixed models with EF, diet order, and period as fixed effects and participant as random effect were used to estimate the intervention effect. Interaction effects between EF and body fat percentage were examined. ResultsAmong the 50 participants who completed the trial, 39 (78%) were women, 30 (60%) were Non-Hispanic White, and 40 (80%) had a body mass index of <25 kg/m2, and the mean age was 32.1 y. The differences between high and low EF in fasting ghrelin (geometric mean difference: 17.76 ng/mL; P = 0.60), leptin (geometric mean difference: 2.09 ng/mL; P = 0.14), adiponectin (geometric mean difference: 381.7 ng/mL; P = 0.32), and hs-CRP (geometric mean difference: −0.018 mg/dL; P = 0.08) were not statistically significant. No significant interaction was observed between EF and body fat percentage on appetite regulation and inflammatory biomarkers. ConclusionsNo differences was observed in fasting ghrelin, leptin, adiponectin, and hs-CRP comparing high and low EF. Future studies are needed to understand the physiology of EF and appetite as they relate to metabolic health.This trial was registered at clinicaltrials.gov as NCT02392897.

Tracking bioaerosol exposure among municipal solid waste workers using hematological and inflammatory biomarkers

High levels of bioaerosols may exist in the air of municipal solid waste (MSW) management facilities, constituting a significant occupational hazard for workers. In this study, we investigated the potential association between exposure to bioaerosols and inflammatory biomarkers among municipal solid waste workers (MSWWs) at both the landfill site and the municipal solid waste transfer station (MSWTS), in comparison to a control group without exposure. Air sampling was conducted at six points around the landfill, two points at the MSWTS, and one point in a public park (as a control area) during the spring and summer of 2019. The results of our study revealed that airborne pathogens were highly prevalent at the sampling points, especially in the active zone and leachate collection pond. Aspergillus species were the predominant fungal species detected in this study, with the highest occurrence observed for Aspergillus flavus (83.3%), Aspergillus niger, and Aspergillus fumigatus (75.0%). Furthermore, Staphylococcus species accounted for over 75% of the total bacterial bioaerosols detected across all study areas. The blood test results of workers revealed a significant increase in platelets (PLT), immunoglobulin G (IgG), white blood cells (WBC), neutrophils, basophils, and high-sensitivity C-reactive protein (hs-CRP) compared to the control group. Conversely, platelet distribution width (PDW), mean platelet volume (MPV), and platelet-large cell ratio (P-LCR) in the exposed subjects exhibited a decreasing trend compared to the control group. These findings suggest a potential association between exposure to bioaerosols, particularly in the vicinity of open dumpsites, and elevated levels of hematologic and inflammatory markers in circulation. Furthermore, the influence of smoking status and confounding factors appears to be significant in both the control and exposure groups.

Inflammation and weight change related to neurocognitive and functional impairment in diabetes and psychiatric disorders

Introduction: Obesity is a global pandemic associated with various cardio-metabolic and psychiatric disorders. Neurocognitive and functional deficits have been associated with several somatic and psychiatric disorders. Adiposity-related inflammation has recently emerged as a key risk factor for neurocognitive and functional impairments. This prospective transdiagnostic study aimed to investigate the role of adiposity-related inflammatory markers in neurocognitive and functional outcomes associated with weight changes.Methods: Peripheral blood inflammatory and oxidative stress biomarkers and neurocognitive and functional performance were assessed twice over 1 year in 165 individuals, including 30 with schizophrenia, 42 with bipolar disorder, 35 with major depressive disorder, 30 with type 2 diabetes mellitus (T2DM), and 28 healthy controls. Participants were stratified by body mass index into categories of type 2 obesity (T2OB; n=30), type 1 obesity (T1OB; n=42), overweight (OW; n=53), and average weight (NW; n=40). Mixed one-way analysis of covariance and linear and binary logistic regression analyses were performed.Results: Compared with NW, T2OB and T1OB were significantly associated with impaired neurocognitive and functional performance (p<0.01; η²p=0.06–0.12) and higher levels of C-reactive protein and platelets (PLT) (p<0.01; η²p= 0.08–0.16), with small-to-moderate effect sizes. IL-6, IL-10, and PLT were key factors for detecting significant weight changes in T1OB and T2OB over time. Regression models revealed that inflammatory and oxidative stress biomarkers and cellular adhesion molecules were significantly associated with neurocognitive and functional performance (p<0.05).Discussion: Obesity is characterised by neurocognitive and functional impairments alongside low-grade systemic inflammation. Adiposity-related inflammatory biomarkers may contribute to neurocognitive and functional decline in individuals with T2DM and psychiatric disorders. Our data suggest that these biomarkers facilitate the identification of specific subgroups of individuals at higher risk of developing obesity.

Social health and subsequent cognitive functioning in people aged 50 years and older: examining the mediating roles of depressive symptoms and inflammatory biomarkers in two European longitudinal studies

Social health markers, including marital status, contact frequency, network size, and social support, have been shown to be associated with cognition. However, the mechanisms underlying these associations remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. In the English Longitudinal Study of Ageing (ELSA), a nationally representative longitudinal study in England, UK, we sampled 7136 individuals aged 50 years or older living in private households without dementia at baseline or at the intermediate mediator assessment timepoint, who had recorded information on at least one social health marker and potential mediator. We used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein, and fibrinogen mediated associations between social health and subsequent standardised cognition (verbal fluency and delayed and immediate recall), including cognitive change, with slopes derived from multilevel models (12-year slope). We examined whether findings were replicated in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study in Sweden, in a sample of 2604 individuals aged 60 years or older living at home or in institutions in Kungsholmen (central Stockholm) without dementia at baseline or at the intermediate mediator assessment timepoint (6-year slope). Social health exposures were assessed at baseline, potential mediators were assessed at an intermediate timepoint (wave 2 in ELSA and 6-year follow-up in SNAC-K); cognitive outcomes were assessed at a single timepoint (wave 3 in ELSA and 12-year follow-up in SNAC-K), and cognitive change (between waves 3 and 9 in ELSA and between 6-year and 12-year follow-ups in SNAC-K). The study sample included 7136 participants from ELSA, of whom 3962 (55·5%) were women and 6934 (97·2%) were White; the mean baseline age was 63·8 years (SD 9·4). Replication analyses included 2604 participants from SNAC-K, of whom 1604 (61·6%) were women (SNAC-K did not collect ethnicity data); the mean baseline age was 72·3 years (SD 10·1). In ELSA, we found indirect effects via depressive symptoms of network size, positive support, and less negative support on subsequent verbal fluency, and of positive support on subsequent immediate recall (pure indirect effect [PIE] 0·002 [95% CI 0·001-0·003]). Depressive symptoms also partially mediated associations between less negative support and slower decline in immediate recall (PIE 0·001 [0·000-0·002]) and in delayed recall (PIE 0·001 [0·000-0·002]), and between positive support and slower decline in immediate recall (PIE 0·001 [0·000-0·001]). We did not observe mediation by inflammatory biomarkers. Findings of mediation by depressive symptoms in the association between positive support and verbal fluency and between positive support and change in immediate recall were replicated in SNAC-K. The findings of this study provide new insights into mechanisms linking social health with cognition, suggesting that associations between interactional aspects of social health, especially social support, and cognition are partly underpinned by depressive symptoms. EU Joint Programme-Neurodegenerative Disease Research (JPND) and Alzheimer's Society. For the Swedish translation of the abstract see Supplementary Materials section.

A Novel Syndrome of Silent Rhinovirus-associated Bronchoalveolitis in Children with Recurrent Wheeze

BackgroundRhinovirus (RV) infections trigger wheeze episodes in children. Thus, understanding of the lung inflammatory response to RV in children with wheeze is important. ObjectiveTo examine the associations of RV on lung lavage (BAL) granulocyte patterns and biomarkers of inflammation with age in children with treatment-refractory, recurrent wheeze (n=616). MethodsChildren underwent BAL to examine viral nucleic acid sequences, bacterial cultures, granulocyte counts, and phlebotomy for both general and type-2 inflammatory markers. ResultsDespite the absence of cold symptoms, RV was the most common pathogen detected (30%), and when present, was accompanied by BAL granulocytosis in 75% of children. Compared to children with no BAL pathogens (n=341), those with RV alone (n=127) had greater (p < 0.05) isolated neutrophilia (43% versus 16%), mixed eosinophils and neutrophils (26% versus 11%), and less pauci-granulocytic (27% versus 61%) BAL. Children with RV alone furthermore had biomarkers of active infection with higher total blood neutrophils and serum c-reactive protein (CRP), but no differences in blood eosinophils or total IgE. With advancing age, the log odds of BAL RV alone were lower, 0.82 [0.76-0.88, p < 0.001], but higher, 1.58 [1.01-2.51, p = 0.04], with high-dose daily corticosteroid treatment. ConclusionsChildren with severe recurrent wheeze often (22%) have a silent syndrome of lung RV infection with granulocytic bronchoalveolitis and elevated systemic markers of inflammation. The syndrome is less prevalent by school age, and not informed by markers of type-2 inflammation. We speculate that dysregulated mucosal innate antiviral immunity is a responsible mechanism.

Young and Older Patients with Acute Myocardial Infarction: Differences in Risk Factors and Angiographic Characteristics

BackgroundAlthough coronary artery disease mainly affects older individuals, the incidence of myocardial infarction (MI) among younger adults (<55 years) has increased during the past decade. Young and older MI patients have different underlying pathophysiologic characteristics, atherosclerotic plaque morphology, and risk factor profiles. MethodsWe studied 977 patients (≤ 55 years old: 322, > 55 years old: 655) who were hospitalized for MI in the previous 5 years. Patients’ baseline characteristics and daily habits were recorded. Angiographic characteristics and vascular lesions were detected, and further examinations, including flow-mediated dilation (FMD), pulse wave velocity (PWV) and central augmentation index (AIx), were performed. Biomarkers of inflammation (Interleukin-6, Tumor-Necrosis factor-a, Intercellular Adhesion Molecule 1, Osteopontin) were also tested. ResultsThe median age in the younger age group was 49 years [interquartile range (IQR: 44-53)] and 66 years (IQR): 61-73) in the older age group. Arterial hypertension was less prevalent in the young compared to the elderly with MI (47.4% vs 76.2%, p < 0.01). The younger counterparts presented significantly lower rates of diabetes mellitus (19.3% vs 30.6%, p <0.01), dyslipidemia (59% vs 70.8%, p <0.01), and atrial fibrillation (2.6% vs 9.7%, p <0.01) and were more casual smokers (49.3% vs 23.8%, p <0.01) compared to older patients with MI. In terms of arterial stiffness, lower PWV [7.3 m/s (IQR: 6.5-8.4 m/s) vs. 9 m/s (IQR: 8-10.8 m/s), p <0.01] and AIx (20.5 ± 10.8 vs 25.5 ± 7.8, p <0.01) were recorded in the young compared to the elderly with MI. Concerning angiographic characteristics, younger patients were more likely to have none or single-vessel disease (55.6% vs 45.8%, p < 0.02), whereas the older participants more frequently had three or more vessel disease (23.5% vs. 13.6% in the young, p < 0.02). Although significant disparities in blood test results were detected during the acute phase, the great majority of young MI patients were undertreated. ConclusionYounger patients with MI are more likely to be smokers with impaired PWV measures, presenting with non-obstructive or single-vessel disease, while they often remain undertreated. A better knowledge of the risk factors as well as the anatomic and pathophysiologic processes in young adults will help enhance MI prevention and treatment options in this patient population.

Alterations in Sarcopenia Index are Associated with Inflammation, Gut and Oral Microbiota among Heart Failure, Left Ventricular Assist Device and Heart Transplant Patients.

BackgroundSarcopenia, characterized by loss of muscle mass and function, is prevalent in heart failure (HF) and predicts poor outcomes. We investigated alterations in sarcopenia index (SI), a surrogate for skeletal muscle mass, in HF, left ventricular assist device (LVAD) and heart transplant (HT), and assessed its relationship with inflammation and digestive tract (gut and oral) microbiota. MethodsWe enrolled 460 HF, LVAD and HT patients. Repeated measures pre/post procedures were obtained prospectively in a subset of LVAD and HT patients. SI (serum Creatinine/Cystatin C) and inflammatory biomarkers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) were measured in 271 and 622 blood samples, respectively. Gut and saliva microbiota were assessed via 16S rRNA sequencing among 335 stool and 341 saliva samples. Multivariable regression assessed the relationship between SI and i) New York Heart Association class; ii) pre- vs. post-LVAD or HT; iii) biomarkers of inflammation and microbial diversity. ResultsMedian (interquartile range) natural logarithm (ln)-SI was -0.13 (-0.32,0.05). Ln-SI decreased across worsening HF class, further declined at 1-month after LVAD and HT and rebounded over time. Ln-SI was correlated with inflammation (r=-0.28, p<0.01), and gut (r=0.28, p<0.01) and oral microbial diversity (r=0.24, p<0.01), these associations remained significant after multivariable adjustment in the combined cohort but not for all individual cohorts. Presence of the gut taxa Roseburia inulinivorans was associated with increased SI. ConclusionsSI levels decreased in symptomatic HF and remained decreased long-term after LVAD and HT. In the combined cohort, SI levels covaried with inflammation in a similar fashion and significantly related to overall microbial (gut and oral) diversity, including specific taxa compositional changes.

A Comparative Evaluation of Prosthetic and Biological Outcome as Influenced by Two Different Implant Restorative Materials (Porcelain Fused to Metal and Monolith Zirconia): A Prospective, Cross-arch Study.

To investigate the prosthetic parameters, clinical indices, crestal bone levels, and inflammatory biomarkers in peri-implant crevicular fluid as influenced by two different implant restorative materials i.e., metal ceramic and monolithic zirconia at baseline, 1 Year and 2 Years. Twenty patients with bilateral implants placed in the same arch were selected. Monolithic zirconia (4Y-PSZ) crown was placed on one side whereas a metal ceramic (M C) crown was inserted on the contralateral side after randomization. Interproximal marginal bone level (MBL), clinical parameters, MMP-8 levels in PICF, and prosthetic characteristics (as determined by modified USPHS criteria) were evaluated at baseline, 1-year, and 2-year follow-ups. Data were descriptively examined. The results were evaluated using the Chi-Square Test, ANOVA, and student t-test. At p < .05., statistical significance was determined. Twenty MC crowns and twenty Mono-ZrO2 crowns were delivered. A 100% survival of the implants and the prosthetic crowns was achieved across all patients with no instances of failure noted throughout the two-year follow-up period. The periodontal changes observed in the participants were analysed and demonstrated statistically insignificant alterations. Prosthetic alterations were assessed according to USPHS criteria, revealing minor ceramic chippings and instances of screw loosening within the MC group during both the 1- and 2-year follow-up periods. These incidents were collectively categorized as technical issues. Regarding anatomical form and color match to the surrounding dentition, the Mono- ZrO2 crowns obtained much lower evaluations when compared to the M-C crowns. However, when evaluating the loss of marginal bone and level of inflammatory markers there were no discernible variations between the groups. The null hypothesis that there is no similarity in the survival rates and interactions at the peri-implant interface between the two types of restorations was rejected. Both monolithic zirconia and metal ceramic crowns demonstrated no statistical differences across all parameters examined in the present prospective investigation.

Inflammatory biomarkers and risk for preeclampsia development

Inflammatory biomarkers and risk for preeclampsia development

Proteomics early after heart transplantation and relation to coronary intimal changes and prognosis - an exploratory study

BackgroundLong-term survival after heart transplantation (HTx) is limited by cardiac allograft vasculopathy (CAV). The pathogenesis of CAV is poorly understood, and treatment has not yet been well-established. In this exploratory study, we aimed to identify novel immune and non-immune biomarkers correlated to CAV development, and biomarkers predicting CAV related events. MethodsUsing a proteomic panel, 92 cardiovascular disease-related proteins were evaluated in 26 de novo HTx patients at 3- and 12-months post transplantation. Intima area changes were assessed using optical coherence tomography (OCT). Major adverse cardiac events (MACE) included significant CAV progression, heart failure, and cardiovascular death. ResultsMedian follow up was 6.8 years. We found changes in four inflammatory biomarkers: Matrix metalloproteinase 3 (MMP-3) and matrix metalloproteinase 2 (MMP-2) were significantly increased after 3 months in the group of patients with highest intima proliferation, and after 12 months in patients experiencing MACE, respectively. Monocyte chemotactic protein 1 (MCP-1) was increased after 12 months in patients experiencing MACE. Platelet derived growth factor subunit A (PDGF-A) was significantly increased after 3 months in the group of patients with highest intima proliferation. ConclusionsWe identified four biomarkers that may be associated with CAV development which differed significantly between groups of intima proliferation and MACE; MMP-2, MMP-3, MCP-1 and PDGF-A. Further studies are needed to examine whether our findings offer the basis to seek for new markers of graft vasculopathy or treatment options.

Epigenetic and biological age acceleration in children with atopic dermatitis

BackgroundAtopic dermatitis is a chronic inflammatory skin disease resulting from the complex interplay of genetic and environmental factors, meriting exploration using temporally-dynamic biomarkers. DNA methylation-based algorithms have been trained to accurately estimate biological age, and deviation of predicted age from true age (epigenetic age acceleration) has been implicated in several inflammatory diseases, including asthma. ObjectiveTo determine the role of epigenetic and biological aging, telomere length, and epigenetically-inferred abundance of seven inflammatory biomarkers in atopic dermatitis. MethodsWe performed DNA methylation-based analyses in a pediatric atopic dermatitis cohort (n=24, mean age 2.56±0.28y) and age-matched healthy subjects (n=24, mean age 2.09±0.15y) derived from blood, using five validated algorithms that assess epigenetic (Horvath, Skin&Blood) and biological age (PhenoAge, GrimAge), telomere length (TelomereLength), and inflammatory biomarker levels. ResultsEpigenetic and biological age, but not telomere length, were accelerated in atopic dermatitis patients for four algorithms: Horvath (+0.88 years; 95%CI 0.33-1.4; p=2.3x10-3), Skin&Blood (+0.95 years; 95%CI 0.67-1.2; p=1.8x10-8), PhenoAge (+8.2 years; 95%CI 3.4-13.0; p=1.3x10-3), and GrimAge (+1.8 years 95%CI 0.22-3.3; p=0.026). Moreover, patients had increased levels of beta-2-microglobulin (+47,584.4 ng/ml; p=0.029), plasminogen activation inhibitor 1 (+3,432.9 ng/ml; p=1.1x10-5) and cystatin C (+31,691 ng/ml; p=4.0x10-5), while levels of tissue inhibitor metalloproteinase 1 (-370.7 ng/ml; p=7.5x10-4) were decreased versus healthy subjects. ConclusionDNA methylation changes associated with epigenetic and biological aging, and inflammatory proteins appear early in life in pediatric atopic dermatitis and may be relevant clinical biomarkers of pathophysiology.

The beneficial effects of neutrophil elastase inhibitor on gastrointestinal dysfunction in sepsis.

To investigate the effects of neutrophil elastase inhibitor (sivelestat sodium) on gastrointestinal function in sepsis. A reanalysis of the data from previous clinical trials conducted at our center was performed. Septic patients were divided into either the sivelestat group or the non-sivelestat group. The gastrointestinal dysfunction score (GIDS), feeding intolerance (FI) incidence, serum levels of intestinal barrier function and inflammatory biomarkers were recorded. The clinical severity and outcome variables were also documented. A total of 163 septic patients were included. The proportion of patients with GIDS ≥2 in the sivelestat group was reduced relative to that in the non-sivelestat group (9.6% vs. 22.5%, p = 0.047) on the 7th day of intensive care unit (ICU) admission. The FI incidence was also remarkably reduced in the sivelestat group in contrast to that in the non-sivelestat group (21.2% vs. 37.8%, p = 0.034). Furthermore, the sivelestat group had fewer days of FI [4 (3, 4) vs. 5 (4-6), p = 0.008]. The serum levels of d-lactate (p = 0.033), intestinal fatty acid-binding protein (p = 0.005), interleukin-6 (p = 0.001), white blood cells (p = 0.007), C-reactive protein (p = 0.001), and procalcitonin (p < 0.001) of the sivelestat group were lower than those of the non-sivelestat group. The sivelestat group also demonstrated longer ICU-free days [18 (0-22) vs. 13 (0-17), p = 0.004] and ventilator-free days [22 (1-24) vs. 16 (1-19), p = 0.002] compared with the non-sivelestat group. In conclusion, sivelestat sodium administration appears to improve gastrointestinal dysfunction, mitigate dysregulated inflammation, and reduce disease severity in septic patients.

Concurrent alteration in the inflammatory biomarkers at gene and protein level by fucoxanthin in liver injury rat

Concurrent alteration in the inflammatory biomarkers at gene and protein level by fucoxanthin in liver injury rat

Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (β±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Efficacy assessment of novel methanimine derivatives in chronic constriction injury-induced neuropathic model: An in-vivo, ex-vivo and In-Silico approach

The multicomponent etiology, complex clinical implications, dose-based side effect and degree of pain mitigation associated with the current pharmacological therapy is incapable in complete resolution of chronic neuropathic pain patients which necessitates the perpetual requirement of novel medication therapy. Therefore, this study explored the ameliorative aptitude of two novel methanimine imitative like (E)-N-(4-nitrobenzylidene)-4‑chloro-2-iodobenzamine (KB 09) and (E)-N-(4-methylbenzylidene)-4‑chloro-2-iodobenzamine (KB 10) in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rat model. Standard behavioral tests like dynamic and static allodynia, cold, thermal and mechanical hyperalgesia along with rotarod activity were performed at various experimental days like 0, 3, 7, 14 and 21. Enzyme linked immunosorbent assay (ELISA) on spinal tissue and antioxidant assays on sciatic nerve were executed accompanied by molecular docking and simulation studies. Prolonged ligation of sciatic nerve expressively induced hyperalgesia as well as allodynia in rats. KB 09 and KB 10 substantially attenuated the CCI elicited hyperalgesia and allodynia. They significantly reduced the biomarkers of pain and inflammation like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in ELISA and while enhanced the GSH, SOD and CAT and diminished the MDA levels during antioxidant assays. KB 09 displayed -9.62 kcal/mol with TNF-α and -7.68 kcal/mol binding energy with IL-6 whereas KB 10 exhibited binding energy of -8.20 kcal/mol with IL-6 while -11.68 kcal/mol with TNF-α and hence both trial compounds ensured stable interaction with IL-6 and TNF-α during computational analysis. The results advocated that both methanimine derivatives might be novel candidates for attenuation of CCI-induced neuropathic pain prospects via anti-nociceptive, anti-inflammatory and antioxidant mechanisms.