Inflammation Of Blood Vessels Research Articles

Extracellular SOD modulates canonical TNFα signaling and α5β1 integrin transactivation in vascular smooth muscle cells

TNFα activates NADPH oxidase 1 (Nox1) in vascular smooth muscle cells (VSMCs). The extracellular superoxide anion (O2•-) produced is essential for the pro-inflammatory effects of the cytokine but the specific contributions of O2•- to signal transduction remain obscure. Extracellular superoxide dismutase (ecSOD, SOD3 gene) is a secreted protein that binds to cell surface heparin sulfate proteoglycans or to Fibulin-5 (Fib-5, FBLN5 gene), an extracellular matrix protein that also associates with elastin and integrins. ecSOD converts O2•- to hydrogen peroxide (H2O2) which prevents NO• inactivation, limits generation of hydroxyl radical (OH•), and creates high local concentrations of H2O2. We hypothesized that ecSOD modifies TNFα signaling in VSMCs. Knockdown of ecSOD (siSOD3) suppressed downstream TNFα signals including MAPK (JNK and ERK phosphorylation) and NF-κB activation (luciferase reporter and IκB phosphorylation), interleukin-6 (IL-6) secretion, iNOS and VCAM expression, and proliferation (Sulforhodamine B assay, PCNA western blot). These effects were associated with significant reductions in the expression of both Type1 and 2 TNFα receptors. Reduced Fib-5 expression (siFBLN5) similarly impaired NF-κB activation by TNFα, but potentiated FAK phosphorylation at Y925. siSOD3 also increased both resting and TNFα-induced phosphorylation of FAK and of glycogen synthase kinase-3β (GSK3β), a downstream target of integrin linked kinase (ILK). These effects were dependent upon α5β1 integrins and siSOD3 increased resting sulfenylation (oxidation) of both integrin subunits, while preventing TNFα-induced increases in sulfenylation. To determine how ecSOD modified TNFα-induced inflammation in intact blood vessels, mesenteric arteries from VSMC-specific ecSOD knockout (KO) mice were exposed to TNFα (10 ng/ml) in culture for 48 h. Relaxation to acetylcholine and sodium nitroprusside was impaired in WT but not ecSOD KO vessels. Thus, ecSOD association with Fib-5 supports pro-inflammatory TNFα signaling while tonically inhibiting α5β1 integrin activation.

Complex case of systemic vasculitis

Vasculitis is a general term that defines a combined group of diseases based on immunopathological inflammation of blood vessels — arteries, arterioles, capillaries, venules, and veins. As a rule, the consequence of this disease is a change in the structure and function of organs supplied with blood by inflamed vessels. The causes of the disease remain unknown. A combination of genetic predisposition with environmental factors, as well as infections involving Staphylococcus aureus or hepatitis virus, are suspected. The article presents a case of systemic vasculitis, which required a complex differential diagnostic search and timely choice of treatment tactics.

FRI114 PUFAs Implicated In Platelet Activation Differ In Receptor Mediated Vs Post-receptor Insulin Resistance

Abstract Disclosure: R. Klein: None. S.T. Chung: None. R.J. Brown: None. Background: Severe insulin resistance (IR) can be classified as receptor mediated, in which all downstream signaling is blocked, or post receptor IR where some downstream signaling pathways are decreased and others are increased. Receptor-mediated IR occurs in rare mutations of the insulin receptor (INSR), whereas in most forms of IR, including type 2 diabetes (T2DM) and lipodystrophy (LD), IR is post-receptor. LD is a group of syndromes characterized by deficiency of fat depots leading to metabolic dysfunction similar to obesity. Patients with post-receptor IR have increased atherosclerotic cardiovascular disease (ASCVD) risk. Thrombosis underlies pathology of ASCVD and is a result of platelet (PLT) activation. Polyunsaturated fatty acids (PUFAs) are embedded in the PLT membrane and play a key role in thrombosis. During PLT activation, cytosolic phospholipase A2 (cPLA2) hydrolyzes membrane lipids, generating free PUFAs, leading to synthesis of mediators of blood vessel constriction, inflammation, and thrombosis. Methods: This was a cross-sectional study of subjects with INSR (N=30) and LD (N=30) matched for age, sex, HbA1c and pubertal stage. Untargeted metabolomic (848 compounds) and lipidomic (984 compounds) analysis was completed on serum after an 8-12 hour fast. Analyses were conducted by t-test and Mann-Whitney with adjustment for multiplicity. Bonferroni corrected P<0.05 was considered significant. Results: Of 19 long chain PUFAs (ω=3, ω=6) measured, 14 were significantly elevated in LD vs INSR, including arachidonate, docosahexaenoate, docosapentaenoate, stearidonate, and adrenate. There was no difference in linoleate, dihomo-linoleate, tetradecadienoate, linolenate, or docosadienoate levels between LD vs INSR. Among 8 long chain saturated FAs, only 3 were significantly higher in LD, 4 were comparable, and 1 was higher in INSR. All long and medium chain monounsaturated FAs were similar in LD vs INSR. cPLA2 was not different between LD and INSR. Conclusions: Our study shows that liberated PUFAs were higher in the patients with LD compared to INSR. A similar trend was not seen for other FFA such as saturated and monounsaturated FFA, suggesting that higher PUFAs in LD are unlikely to be caused by global differences in FFA metabolism, such as different peripheral uptake of FFA via lipoprotein lipase activity or diet. Instead, our data suggest an increase in PLT membrane ability to store and release PUFAs. These data suggest increased ASCVD risk in post-receptor insulin resistance may be partially mediated through differences in platelet activation. Presentation: Friday, June 16, 2023

Human BBB-on-a-chip reveals barrier disruption, endothelial inflammation, and T cell migration under neuroinflammatory conditions.

The blood-brain barrier (BBB) is a highly selective barrier that ensures a homeostatic environment for the central nervous system (CNS). BBB dysfunction, inflammation, and immune cell infiltration are hallmarks of many CNS disorders, including multiple sclerosis and stroke. Physiologically relevant human in vitro models of the BBB are essential to improve our understanding of its function in health and disease, identify novel drug targets, and assess potential new therapies. We present a BBB-on-a-chip model comprising human brain microvascular endothelial cells (HBMECs) cultured in a microfluidic platform that allows parallel culture of 40 chips. In each chip, a perfused HBMEC vessel was grown against an extracellular matrix gel in a membrane-free manner. BBBs-on-chips were exposed to varying concentrations of pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β) to mimic inflammation. The effect of the inflammatory conditions was studied by assessing the BBBs-on-chips' barrier function, cell morphology, and expression of cell adhesion molecules. Primary human T cells were perfused through the lumen of the BBBs-on-chips to study T cell adhesion, extravasation, and migration. Under inflammatory conditions, the BBBs-on-chips showed decreased trans-endothelial electrical resistance (TEER), increased permeability to sodium fluorescein, and aberrant cell morphology in a concentration-dependent manner. Moreover, we observed increased expression of cell adhesion molecules and concomitant monocyte adhesion. T cells extravasated from the inflamed blood vessels and migrated towards a C-X-C Motif Chemokine Ligand 12 (CXCL12) gradient. T cell adhesion was significantly reduced and a trend towards decreased migration was observed in presence of Natalizumab, an antibody drug that blocks very late antigen-4 (VLA-4) and is used in the treatment of multiple sclerosis. In conclusion, we demonstrate a high-throughput microfluidic model of the human BBB that can be used to model neuroinflammation and assess anti-inflammatory and barrier-restoring interventions to fight neurological disorders.

Intra-Cranial Arterial Calcifications in Hemodialysis Patients.

Background and objectives: Vascular calcification is an integral part of atherosclerosis and has been reported to be an independent risk factor for cardiovascular diSsease. Intra Cranial Arterial Calcifications (ICAC) in maintenance hemodialysis (MHD) is highly prevalent. Materials and Methods: The aim of this retrospective study was to assess the predictors and outcomes of ICAC in MHD patients compared to a control group without kidney disease. A blinded neuroradiologist graded ICAC in brain imaging (computerized tomography) of MHD patients. Age- and sex-matched patients with normal kidney function served as the control group. Results: A total of 280 patients were included in the cohort; 140 of them were MHD patients with a mean ICAC score of 2.3 ± 0.2 versus a mean ICAC score of 1.4 ± 0.2 in the control group (p < 0.01). More than 90% of hemodialysis patients in our study had some degree of ICAC. Lower albumin and higher phosphorus and CRP levels were associated with increased ICACs. The multivariate analysis model for predictors of 1-year mortality demonstrated an increased odds ratio for mortality as the ICAC score increased. Conclusions: ICAC is very prevalent among MHD patients and results not simply from passive deposition of calcium and phosphate but rather from complex and active processes involving inflammation and structural changes in blood vessels. ICAC independently predicted all-cause mortality and may help with risk stratification of this high-risk population.

Animal models for anti-neutrophil cytoplasmic antibody-associated vasculitis: Are current models good enough?

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a rare and severe systemic autoimmune disease characterized by pauci-immune necrotizing inflammation of small blood vessels. AAV involves multiple organ systems throughout the body. Our knowledge of the pathogenesis of AAV has increased considerably in recent years, involving cellular, molecular and genetic factors. Because of the controlled environment with no other confounding factors, animal models are beneficial for studying the mechanistic details of disease development and for providing novel therapeutic targets with fewer toxic side effects. However, the complexity and heterogeneity of AAV make it very difficult to establish a single animal model that can fully represent the entire clinical spectrum found in patients. The aim of this review is to overview the current status of animal models for AAV, outline the pros and cons of methods, and propose potential directions for future research.

Identification and Quantitation of the Bioactive Components in Wasted Aralia elata Leaves Extract with Endothelial Protective Activity.

Aralia elata, a renowned medicinal plant with a rich history in traditional medicine, has gained attention for its potential therapeutic applications. However, the leaves of this plant have been largely overlooked and discarded due to limited knowledge of their biological activity and chemical composition. To bridge this gap, a comprehensive study was conducted to explore the therapeutic potential of the 70% ethanol extract derived from Aralia elata leaves (LAE) for the treatment of cardiovascular disease (CVD). Initially, the cytotoxic effects of LAE on human umbilical vein endothelial cells (HUVECs) were assessed, revealing no toxicity within concentrations up to 5 μg/mL. This suggests that LAE could serve as a safe raw material for the development of health supplements and drugs aimed at promoting cardiovascular well-being. Furthermore, the study found that LAE extract demonstrated anti-inflammatory properties in HUVECs by modulating the PI3K/Akt and MAPK signaling pathways. These findings are particularly significant as inflammation plays a crucial role in the progression of CVD. Moreover, LAE extract exhibited the ability to suppress the expression of adhesion molecules VCAM-1 and ICAM-1, which are pivotal in leukocyte migration to inflamed blood vessels observed in various pathological conditions. In conjunction with the investigation on therapeutic potential, the study also established an optimal HPLC-PDA-ESI-MS/MS method to identify and confirm the chemical constituents present in 24 samples collected from distinct regions in South Korea. Tentative identification revealed the presence of 14 saponins and nine phenolic compounds, while further analysis using PCA and PLS-DA allowed for the differentiation of samples based on their geographical origins. Notably, specific compounds such as chlorogenic acid, isochlorogenic acid A, and quercitrin emerged as marker compounds responsible for distinguishing samples from different regions. Overall, by unraveling its endothelial protective activity and identifying key chemical constituents, this research not only offers valuable insights for the development of novel treatments but also underscores the importance of utilizing and preserving natural resources efficiently.

345-OR: Exercise and Liraglutide Synergistically Attenuate Vascular Inflammation and Enhance Metabolic Insulin Action in Diet-Induced Obesity

Endothelial oxidative stress and vascular inflammation induce microvascular insulin resistance which is an early event in diet-induced obesity and contributes to metabolic insulin resistance. To examine whether exercise and glucagon-like peptide 1 (GLP-1) receptor agonism, alone or in combination, modulate vascular and metabolic insulin actions during obesity development, we performed an euglycemic insulin clamp, in conjunction with contrast enhanced ultrasound, in adult male rats after 2 weeks of high-fat diet feeding with either access to running wheel (exercise), liraglutide (200 mg/kg subcutaneously twice daily), or the combination of both. Rats exhibited increased visceral adiposity and blunted microvascular responses (microvascular blood volume, flow velocity, and total flow) and metabolic insulin actions (glucose infusion rates). Exercise and liraglutide alone each improved muscle insulin sensitivity but their combination fully restored insulin-mediated glucose infusion rates. The combined exercise and liraglutide intervention enhanced insulin-mediated muscle microvascular perfusion, reduced perivascular macrophage accumulation and oxidative stress in the muscle, attenuated blood vessel inflammation and improved endothelial function, along with increased nucleus translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and phosphorylation of AMP-activated protein kinase (AMPK) and nitric oxide synthase (eNOS) in endothelial cells. We conclude that exercise and liraglutide synergistically enhance the metabolic actions of insulin and reduce vascular oxidative stress and inflammation in the early stage of obesity development. Our data suggest that early combination use of exercise and GLP-1 receptor agonism might be an effective strategy in preventing microvascular and metabolic insulin resistance and associated complications during the development of obesity. Disclosure J.Liu: None. K.W.Aylor: None. Z.Liu: None. Funding National Institutes of Health (R01DK125330), (R01DK1124344 to Z.L.)

Kawasaki Disease in Children

Kawasaki Disease (KD), previously defined as mucocutaneous lymph node syndrome, is a febrile illness caused by inflammation of the body's medium-sized blood vessels. Tomisaku Kawasaki first described it in 1967 as a self-limited acute vasculitic syndrome of unknown etiology. Intravenous immunoglobulin (IV) and high-dose oral aspirin should be begun within 10 days of disease onset along with aspirin.

Outcomes in ANCA-Associated Vasculitis in Scotland: Validation of the Renal Risk Score in a Complete National Cohort

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) causes autoimmune-mediated inflammation of small blood vessels in multiple organs, including the kidneys. The ability to accurately predict kidney outcomes would enable a more personalized therapeutic approach. We used our national renal biopsy registry to validate the ability of ANCA Renal Risk Score (ARRS) to predict end-stage kidney disease (ESKD) for individual patients. This score uses histopathological and biochemical data to stratify patients as high, medium, or low risk for developing ESKD. A total of 288 patients were eligible for inclusion in the study (low risk n= 144, medium risk n= 122, high risk n= 12). Using adjusted Cox proportional hazard models with the low-risk group as reference, we show that outcome differs between the categories: high-risk hazard ratio (HR) 16.69 (2.91-95.81, P= 0.002); medium risk HR 4.14 (1.07-16.01, P= 0.039). Incremental multivariable-adjusted Cox proportional hazards models demonstrated that adding ARRS to a model adjusted for multiple clinical parameters enhanced predictive discrimination (basic model C-statistic 0.864 [95% CI 0.813-0.914], basic model plus ARRS C-statistic 0.877 [95% CI 0.823-0.931]; P<0.01). The ARRS better discriminates risk of ESKD in AAV and offers clinicians more prognostic information than the use of standard biochemical and clinical measures alone. This is the first time the ARRS has been validated in a national cohort. The proportion of patients with high-risk scores is lower in our cohort compared to others and should be noted as a limitation of this study.

A Case of C-ANCA Associated Vasculitis Presenting With Localised Skin Thickening

ANCA vasculitis, caused by antibodies named ANCA (anti-neutrophilic cytoplasmic autoantibodies), is an autoimmune disorder affecting small blood vessels of the body. Among p-ANCA and c- ANCA, c-ANCA (cytoplasmic ANCA) usually targets proteinase three inside neutrophils, causing inflammation of blood vessels. Herein, we report a case of a 56-year-old female patient with c- ANCA-associated vasculitis. The patient presented with a localized skin thickening on the medial aspect of the left thigh and an oral ulcer. Skin biopsy shows erythema induratum (nodular vasculitis). After several investigations, we found c-ANCA positive and concluded the diagnosis as c-ANCA-associated vasculitis. We treat the patient with injectable methylprednisolone, injectable cyclophosphamide, and Mesna. Then we gave oral mycophenolate mofetil and prednisolone. J Dhaka Med Coll. 2022; 31(1) : 158-162

Cargo-free particles divert neutrophil-platelet aggregates to reduce thromboinflammation

The combination of inflammation and thrombosis is a hallmark of many cardiovascular diseases. Under such conditions, platelets are recruited to an area of inflammation by forming platelet-leukocyte aggregates via interaction of PSGL-1 on leukocytes and P-selectin on activated platelets, which can bind to the endothelium. While particulate drug carriers have been utilized to passively redirect leukocytes from areas of inflammation, the downstream impact of these carriers on platelet accumulation in thromboinflammatory conditions has yet to be studied. Here, we explore the ability of polymeric particles to divert platelets away from inflamed blood vessels both in vitro and in vivo. We find that untargeted and targeted micron-sized polymeric particles can successfully reduce platelet adhesion to an inflamed endothelial monolayer in vitro in blood flow systems and in vivo in a lipopolysaccharide-induced, systemic inflammation murine model. Our data represent initial work in developing cargo-free, anti-platelet therapeutics specifically for conditions of thromboinflammation.

Influence of smoking on disease activity and prognosis of antineutrophil cytoplasmic antibody-associated vasculitis: a retrospective cohort study.

Antineutrophil cytoplasmic antibody-associated vasculitides (AAV) are a group of autoimmune diseases characterized by inflammation of small blood vessels. Smoking is a potential trigger for such diseases, however, its link with AAV remains controversial. The aim of this study was to analyze the link between AAV and smoking based on clinical characteristics, disease activity, and mortality. This retrospective study included 223 AAV patients. Their smoking status was assessed at diagnosis and they were classified as ever smokers (ESs), including current or past smokers, and never smokers (NSs). Information regarding clinical presentation, the disease activity, immunosuppressive therapy, and survival was collected. The ESs had similar organ involvement to the NSs, except for significantly greater frequency of renal replacement therapy (31% vs 14%; P = 0.003). Median (interquartile range [IQR]) time from symptom onset to diagnosis was significantly shorter in the ESs than the NSs (4 [2-9.5] vs 6 [3-13] months; P = 0.03), with significantly higher mean (SD) value of the Birmingham Vasculitis Activity Score version 3 (19.5 [7.93] vs 17.25 [8.05]; P = 0.04). The ESs were more likely to receive cyclophosphamide therapy (P = 0.03), and had significantly higher morality than the NSs (hazard ratio, 2.89; 95% CI, 1.47-5.72; P = 0.002). There were no significant differences between the current and past smokers. The multivariable Cox proportional regression analysis found ever smoking and male sex to be independent predictors of mortality in AAV patients. Ever smoking is associated with increased AAV activity and more frequent renal replacement therapy and immunosuppressive treatment, resulting in a poorer survival prognosis in AAV patients. Future multicenter studies are required to further characterize the clinical, biological, and prognostic impact of smoking on AAV.

Artemisin and human endometrial-derived stem cells improve cognitive function and synaptic plasticity in a rat model of Alzheimer disease and diabetes.

Alzheimer disease (AD) is a common form of dementia associated with loss of memory and disruption of synaptic plasticity. There is a strong correlation between the pathophysiological features of AD and diabetes, including induction of oxidative stress, inflammation, and abnormality in blood vessels. Considering the brain's limited capacity to repair damage and the potential of stem cell-derived neural cells in the repair of neurodegenerative disease, we investigated the effects of artemisinin and TSP‑1‑human endometrial-derived-derived stem cells (TSP‑1‑hEDSCs) on the cognitive function and synaptic plasticity in AD-diabetes rats. The authors previously showed that artemisinin and TSP‑1‑hEDSCs suppressed oxidative stress and inflammation in AD-diabetes rats. Thrombospondins-1 (TSPs-1) is a glycoprotein that inhibits angiogenesis. AD and diabetes were induced using streptozotocin. Synaptic plasticity and learning and memory function were studied using the Morris water maze and electrophysiological test, respectively. Streptozotocin increased traveled swimming distance and escape latency in the morris water maze test, decreased the percent time spent in the target quadrant, inhibited the long-term potentiation (LTP), and increased the blood glucose levels. Simultaneous or separate administration of artemisinin and TSP‑1‑hEDSCs decreased the blood levels of glucose and improved cognitive tasks and synaptic plasticity by considerably reducing traveled swimming distance and escape latency, increasing the percent time spent in the target quadrant, and retrieval of the LTP; therefore, they could be utilized as an adjunct treatment for AD treatment. These results may be due to a decrease in oxidative stress and inflammation.

5588568 ASSOCIATION OF MANNOSE-BINDING LECTIN SERUM LEVEL AND PROMOTER GENE VARIANTS RS7096206 AND RS10031251 WITH FREQUENCY OF VASO-OCCLUSIVE EVENTS IN SICKLE CELL DISEASE PATIENTS; AN EGYPTIAN CROSS-SECTIONAL STUDY

Background: Sickle cell disease (SCD) is a genetic blood disorder involving hemoglobin alterations, in addition to endothelial adhesion, thrombosis and inflammation. Low serum Mannose-binding lectin (MBL) levels can enhance SCD-related blood vessel inflammation as well as reduction of phagocytic activity, leading to sickled erythrocyte accumulation on vessel walls and impaired ability to combat infections. This may contribute to the vaso-occlusive (VOC) episodes. Aim: This work aimed to investigate serum MBL level and MBL promoter gene variants distribution among a cohort of Egyptian SCD patients and to describe their association with VOC events frequencies in the studied patients. Methods: This cross-sectional study included 88 steady-state Egyptian SCD patients aged 6-18 years diagnosed and followed up at Pediatric Hematology Unit, Cairo University Children Hospital. Informed consent was obtained willingly from all subjects or their guardians before enrolment in the study. MBL promoter (-221) (rs7096206) X/Y and (-550) (rs10031251) H/L gene variants were studied by Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) technique. Serum MBL level was assayed by ELISA technique with values <500ng/ml considered deficient. Results: The median serum MBL level in SCD patients was 130.9 ng/ml (IQR 71.2-323.9 ng/ml). Patients with serum MBL levels <500ng/ml were significantly older, had longer disease duration and higher rate of VOCs per year, VOCs per lifetime and a higher VOC index (p= 0.039, 0.034, 0.047, 0.040 and 0.008 respectively). Levels <500ng/ml predominated in SS (89.4%) than Sβ groups (70%) (p= 0.023) and in patients with high frequency of VOCs (91.4%) (p=0.008). Serum MBL level correlated negatively with patients’ age, disease duration, hydroxyurea total treatment duration, blood transfusions per lifetime and steady-state HbS level (p= <0.001, <0.001, 0.011, 0.014, 0.031 respectively) but correlated positively with steady-state HbF level (p=0.002). MBL (-221) X/Y both alleles were more associated with (H) allele of MBL (-550) than with L allele (p=0.048), however, with no statistically significant genotype distribution between the studied variants. There was no statistically significant difference in genotype distribution or allele frequencies between MBL (-221) and MBL (-550) in SCD patients regarding serum MBL level, sickle cell type (SS and Sβ), VOCs frequencies or disease severity classes. Conclusion: Serum MBL level rather than studied MBL gene variants is more likely to contribute to the clinical outcomes of SCD; patients with lower MBL levels had a higher rate of VOC per year, per lifetime and a higher VOC index. Meanwhile, the variant genotypes and alleles of the studied MBL promotor gene variants were not associated with MBL deficiency, VOCs, infection events, and disease severity.Further studies to investigate other polymorphisms in MBL gene; MBL exon-1 (codons 52,54 and 57) are recommended. Keywords: MBL, Polymorphism, Sickle cell disease, Vaso-occlusive crises, Egypt

Biomimetic nanoparticles drive the mechanism understanding of shear-wave elasticity stiffness in triple negative breast cancers to predict clinical treatment

In clinical practice, we noticed that triple negative breast cancer (TNBC) patients had higher shear-wave elasticity (SWE) stiffness than non-TNBC patients and a higher α-SMA expression was found in TNBC tissues than the non-TNBC tissues. Moreover, SWE stiffness also shows a clear correlation to neoadjuvant response efficiency. To elaborate this phenomenon, TNBC cell membrane-modified polylactide acid-glycolic acid (PLGA) nanoparticle was fabricated to specifically deliver artesunate to regulate SWE stiffness through inhibiting CAFs functional status. As tested in MDA-MB-231 and E0771 orthotopic tumor models, CAFs functional status inhibited by 231M-ARS@PLGA nanoparticles (231M-AP NPs) had reduced the SWE stiffness as well as attenuated hypoxia of tumor as tumor soil loosening agent which amplified the antitumor effects of paclitaxel and PD1 inhibitor. Single-cell sequencing indicated that the two main CAFs (extracellular matrix and wound healing CAFs) that produces extracellular matrix could influence the tumor SWE stiffness as well as the antitumor effect of drugs. Further, biomimetic nanoparticles inhibited CAFs function could attenuate tumor hypoxia by increasing proportion of inflammatory blood vessels and oxygen transport capacity. Therefore, our finding is fundamental for understanding the role of CAFs on affecting SWE stiffness and drugs antitumor effects, which can be further implied in the potential clinical theranostic predicting in neoadjuvant therapy efficacy through non-invasive analyzing of SWE imaging.

Association Between HLA-DPB1 and Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in Children.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children, with an annual prevalence of 0.5-6.4 cases per million children. The etiology of AAV remains largely unknown, and both environmental and genetic factors are likely involved. The present study was undertaken to explore the genetic susceptibility factors recently identified in adult patients, including HLA-DP and HLA-DQ, in pediatric patients. We performed a genome-wide association study of pediatric AAV in patients of European ancestry (n=63 AAV cases, n=315 population-matched controls). We identified a significant genetic association between pediatric AAV and the HLA-DPB1*04:01 allele (P=1.5 × 10-8 , odds ratio [OR] 3.5), with a stronger association observed in children with proteinase 3-ANCA positivity than in children with myeloperoxidase-ANCA positivity. Among the HLA alleles, the HLA-DPB1*04:01 allele was the most highly associated with AAV, although not significantly, in a follow-up adult AAV cohort (P=2.6 × 10-4 , OR 0.4). T cell receptor and interferon signaling pathways were also shown to be enriched in the pediatric AAV cohort. The HLA-DPB1 locus showed an association with pediatric AAV, as similarly shown previously in adult AAV. Despite the difference in the age of onset, these findings suggest that childhood- and adult-onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies.

Porphyromonas gingivalis regulates atherosclerosis through an immune pathway.

Atherosclerosis (AS) is a chronic inflammatory disease, involving a pathological process of endothelial dysfunction, lipid deposition, plaque rupture, and arterial occlusion, and is one of the leading causes of death in the world population. The progression of AS is closely associated with several inflammatory diseases, among which periodontitis has been shown to increase the risk of AS. Porphyromonas gingivalis (P. gingivalis), presenting in large numbers in subgingival plaque biofilms, is the "dominant flora" in periodontitis, and its multiple virulence factors are important in stimulating host immunity. Therefore, it is significant to elucidate the potential mechanism and association between P. gingivalis and AS to prevent and treat AS. By summarizing the existing studies, we found that P. gingivalis promotes the progression of AS through multiple immune pathways. P. gingivalis can escape host immune clearance and, in various forms, circulate with blood and lymph and colonize arterial vessel walls, directly inducing local inflammation in blood vessels. It also induces the production of systemic inflammatory mediators and autoimmune antibodies, disrupts the serum lipid profile, and thus promotes the progression of AS. In this paper, we summarize the recent evidence (including clinical studies and animal studies) on the correlation between P. gingivalis and AS, and describe the specific immune mechanisms by which P. gingivalis promotes AS progression from three aspects (immune escape, blood circulation, and lymphatic circulation), providing new insights into the prevention and treatment of AS by suppressing periodontal pathogenic bacteria.

Recognizing giant cell arteritis in dental practice

Giant cell arteritis (GCA) is a rare condition that causes inflammation of blood vessels. Early diagnosis and treatment is essential to prevent ischaemic complications, including blindness, tongue necrosis and stroke. GCA can present with orofacial symptoms, such as toothache and pain/difficulty in chewing, which may cause individuals with GCA to first present to the dentist. This has important patient safety and medicolegal implications. Dental practitioners should be alert to the possibility of GCA and should direct suspected cases to their general medical practitioner or a hospital specialist. Increased awareness of GCA should minimize the risk of blindness and stroke. CPD/Clinical Relevance: Early recognition and treatment of GCA is key to prevent complications, such as blindness, tongue necrosis and stroke.

Fabrication of a Novel and Ultrasensitive Label-Free Electrochemical Aptasensor Based on Gold Nanostructure for Detection of Homocysteine

The current attempt was made to detect the amino acid homocysteine (HMC) using an electrochemical aptasensor. A high-specificity HMC aptamer was used to fabricate an Au nanostructured/carbon paste electrode (Au-NS/CPE). HMC at high blood concentration (hyperhomocysteinemia) can be associated with endothelial cell damage leading to blood vessel inflammation, thereby possibly resulting in atherogenesis leading to ischemic damage. Our proposed protocol was to selectively immobilize the aptamer on the gate electrode with a high affinity to the HMC. The absence of a clear alteration in the current due to common interferants (methionine (Met) and cysteine (Cys)) indicated the high specificity of the sensor. The aptasensor was successful in sensing HMC ranging between 0.1 and 30 μM, with a narrow limit of detection (LOD) as low as 0.03 μM.