Systemic Cytokine Research Articles

Amino Acid-Based Beverage Interventions Ameliorate Exercise-Induced Gastrointestinal Syndrome in Response to Exertional-Heat Stress: The Heat Exertion Amino Acid Technology (HEAAT) Study.

The study aimed to determine the effects of two differing amino acid beverage interventions on biomarkers of intestinal epithelial integrity and systemic inflammation in response to an exertional-heat stress challenge. One week after the initial assessment, participants (n = 20) were randomly allocated to complete two exertional-heat stress trials, with at least 1 week washout. Trials included a water control trial (CON), and one of two possible amino acid beverage intervention trials (VS001 or VS006). On VS001 (4.5g/L) and VS006 (6.4g/L), participants were asked to consume two 237-ml prefabricated doses daily for 7days before the exertional-heat stress, and one 237-ml dose immediately before, and every 20min during 2-hr running at 60% maximal oxygen uptake in 35 °C ambient conditions. A water volume equivalent was provided on CON. Whole blood samples were collected pre-, immediately post-, 1 and 2hr postexercise, and analyzed for plasma concentrations of cortisol, intestinal fatty acid protein, soluble CD14, and immunoglobulin M (IgM) by ELISA, and systemic inflammatory cytokines by multiplex. Preexercise resting biomarker concentrations for all variables did not significantly differ between trials (p > .05). A lower response magnitude for intestinal fatty acid protein (mean [95% CI]: 249 [60, 437]pg/ml, 900 [464, 1,336]pg/ml), soluble CD14 (-93 [-458, 272]ng/ml, 12 [-174, 197]ng/ml), and IgM (-6.5 [-23.0, 9.9]MMU/ml, -10.4 [-16.2, 4.7]MMU/ml) were observed on VS001 and V006 compared with CON (p < .05), respectively. Systemic inflammatory response profile was lower on VS001, but not VS006, versus CON (p < .05). Total gastrointestinal symptoms did not significantly differ between trials. Amino acid beverages' consumption (i.e.,4.5-6.4g/L), twice daily for 7days, immediately before, and during exertional-heat stress ameliorated intestinal epithelial integrity and systemic inflammatory perturbations associated with exercising in the heat, but without exacerbating gastrointestinal symptoms.

C-Reactive protein and cognition: Mediation analyses with brain morphology in the UK Biobank

Cognitive impairments and abnormal immune activity are both associated with various clinical disorders. The association between C-Reactive protein (CRP), a marker associated with inflammation, and cognitive performance remains unclear. Further, mechanisms potentially linking CRP to cognition are not yet established. Brain structure may well mediate this relationship: immune processes play crucial roles in shaping and maintaining brain structure, with brain structure and function driving cognition. The United Kingdom Biobank (UKBB) is a large cohort study with extensive assessments, including high-sensitivity serum CRP levels, brain imaging, and various cognitive tasks. With data from 39,200 UKBB participants, we aimed first to determine the relationship between CRP and cognitive performance, and second, to assess metrics of brain morphology as potential mediators in this relationship. Participants were aged 40 to 70 at initial assessment and were mostly Caucasian. After accounting for potential covariates (e.g., age, sex, medical diagnoses, use of selective-serotonin reuptake inhibitors), we found CRP levels to have small, negative associations with fluid intelligence (b = −0.03, 95%CI[-0.05,-0.02], t(14381) = −3.62, pcor = .004), and numeric memory (b = −0.03, 95%CI[-0.05,-0.01], t(14366) = −3.31, pcor = .007). We found no evidence of brain morphology mediating these relationships (all |ab| < 0.001, all pcor > .55). Our findings from this large sample suggest that serum-assessed CRP is of marginal importance for cognitive performance in mid-to-late aged Caucasians; the small effect sizes of statistically significant associations provide context to previous inconsistent results. The seeming lack of involvement of brain morphology suggests that other brain metrics (e.g., connectivity, functional activation) may be more pertinent to this relationship. Future work should also consider CRP levels measured in the central nervous system and/or other cytokines that may better predict cognitive performance in this population.

Sirt6 Activation Ameliorates Inflammatory Bone Loss in Ligature-Induced Periodontitis in Mice.

Periodontitis is an inflammatory disease caused by microorganisms that induce the destruction of periodontal tissue. Inflamed and damaged tissue produces various inflammatory cytokines, which activate osteoclasts and induce alveolar bone loss and, eventually, tooth loss. Sirt6 expression suppresses inflammation and bone resorption; however, its role in periodontitis remains unclear. We hypothesized that Sirt6 has a protective role in periodontitis. To understand the role of Sirt6 in periodontitis, we compared periodontitis with ligature placement around the maxillary left second molar in 8-week-old control (C57BL/6J) male mice to Sirt6-overexpressing Tg (Sirt6Tg) mice, and we observed the resulting phenotypes using micro-CT. MDL801, a Sirt6 activator, was used as a therapy for periodontitis through oral gavage. Pro-inflammatory cytokines and increased osteoclast numbers were observed in alveolar bone tissue under periodontitis surgery. In the same condition, interestingly, protein levels from Sirt6 were the most downregulated among sirtuins in alveolar bone tissue. Based on micro-CT and CEJ-ABC distance, Sirt6Tg was observed to resist bone loss against ligature-induced periodontitis. Furthermore, the number of osteoclasts was significantly reduced in Sirt6Tg-ligated mice compared with control-ligated mice, although systemic inflammatory cytokines did not change. Consistent with this observation, we confirmed that bone loss was significantly reduced when MDL801, a Sirt6 activator, was included in the ligation mouse model. Our findings demonstrate that Sirt6 activation prevents bone loss against ligature-induced periodontitis. Thus, a Sirt6 activator may provide a new therapeutic approach for periodontitis.

Neuroimaging of complications arising after CD19 chimeric antigen receptor T-cell therapy: A review.

Chimeric antigen receptor (CAR) T cells targeting the CD19 (cluster of differentiation 19) cell surface glycoprotein have emerged as a highly effective immunologic therapy in patients with relapsed or refractory B-cell malignancies. The engagement of CAR T cells with CD19 on the surface of neoplastic B cells causes a systemic cytokine release, which can compromise the blood-brain barrier and cause an immune effector cell-associated neurotoxicity syndrome (ICANS). In a small proportion of ICANS patients who demonstrate neuroimaging abnormalities, certain distinct patterns have been recognized, including signal changes in the thalami, external capsule, and brainstem, the subcortical and/or periventricular white matter, the splenium of the corpus callosum, and the cerebellum. On careful review of the underlying pathophysiology of ICANS, we noticed that these changes closely mirror the underlying blood-brain barrier disruption and neuroinflammatory and excitotoxic effects of the offending cytokines released during ICANS. Furthermore, other uncommon complications of CD19 CAR T-cell therapy such as posterior reversible encephalopathy syndrome, ocular complications, and opportunistic fungal infections can be catastrophic if not diagnosed in a timely manner, with neuroimaging playing a significant role in management. In this narrative review, we will summarize the current literature on the spectrum of neuroimaging findings in ICANS, list appropriate differential diagnoses, and explore the imaging features of other uncommon central nervous system complications of CD19 CAR T-cell therapy using illustrative cases from two tertiary care institutions.

#5569 ASSOCIATION OF URINARY CCL14 WITH PLASMA PROTEIN BIOMARKERS IN CRITICALLY ILL SEPSIS PATIENTS WITH PERSISTENT ACUTE KIDNEY INJURY

Abstract Background and Aims The urinary concentration of CC chemokine ligand 14 (CCL14) – a chemoattractant for T-cells and monocytes – has recently been identified as a strong predictor of persistence of severe acute kidney injury (AKI). The mechanisms by which CCL14 mediates persistent severe AKI are not yet completely understood. With sepsis being the most frequent cause of AKI, we wanted to externally validate whether urinary CCL14 concentration can differentiate sepsis patients with and without persistence of AKI, and its association with plasma protein biomarkers reflective of three pathophysiological pathways. Method Patients admitted with sepsis to the intensive care unit (ICU) were categorized according to the evolution of AKI (no-AKI, transient-AKI, and persistent-AKI, defined as lasting &amp;gt; 48h), and matched to a 1:1:1 ratio. AKI was assessed prospectively and daily, using the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification. Transient- and persistent-AKI patients had at least injury or failure (severe) RIFLE stages. Urine samples collected at ICU admission were analyzed for CCL14 level; in the same patient cohort we measured 9 plasma biomarkers reflective of systemic inflammation and cytokine responses, endothelial cell activation, and loss of endothelial barrier function. We applied a recently proposed cutoff of 1.3 ng/mL for high CCL14 for the identification of patients at high risk for persistent severe AKI. Results of 211 sepsis patients enrolled, 72 patients did not have AKI, 71 had transient AKI and 68 had persistent AKI. Majority of patients with high CCL14 had a persistent AKI (23 out of 31; 74.2%). CCL14 showed good discrimination between persistent-AKI and no-AKI (Area Under the ROC Curve [AUC], 0.82, 95%CI 0.75-0.89), and moderate discrimination between persistent-AKI and transient-AKI (AUC 0.71, 95%CI 0.55-0.87). High CCL14 was associated with higher disease severity as measured by APACHE-IV score, and source of infection being the urinary tract, and skin. The plasma protein analysis revealed that high urinary CCL14 was associated with more prominent systemic (anti-)inflammatory and cytokine responses, and signs of disrupted endothelial barrier function (shown by elevated interleukin [IL]-8 and IL-10, and decreased angiopoietin-1 [P = .005; P = .004; P = .009, respectively]). Within the persistent-AKI group, baseline characteristics (age, chronic comorbidities, and disease severity) did not differ between CCL14 groups, and high CCL14 was only associated with decreased angiopoietin-1 (P = .003). Conclusion External validation of urinary CCL14 showed good discrimination in critically ill sepsis patients between persistent AKI and no-AKI, and moderate discriminative ability to separate transient-AKI. High urinary CCL14 identifies persistent-AKI sepsis patients with more profound dysregulation of inflammatory pathways coupled with loss of endothelial barrier function. This could guide future therapeutic strategies targeting subgroups within the AKI population.

Systemic cytokines in elderly patients with coronary heart disease at early recovery from COVID-19

The development of COVID-19 is accompanied by involvement of various cytokines in pathological process. Their change depends on age, concomitant pathology and some other factors that have not been sufficiently studied in elderly patients with coronary heart disease (CHD). The content of cytokines in blood plasma of patients aged 60-74 in the early period of recovery from COVID-19 also remains unknown. The aim of our study was to determine the content of systemic cytokines in elderly patients with coronary heart disease at the early stages of recovery after COVID-19. The patients aged 60-74 with CHD who had COVID-19 of moderate severity grade (n = 40) made up the main group. in which the study of The cytokine levels were studied in blood plasma 3 to 4 weeks after recovery. The control group consisted of 38 elderly patients with coronary heart disease and negative tests for COVID-19. of cytokines in both groups were determined by means of flow cytometry with “Becton Dickinson FACS Canto 2 (USA)” machine using appropriate reagent sets. We have found that, in elderly patients with CHD at 3-4 weeks after recovery from COVID-19, if compared with elderly patients with CHD without COVID-19, the content of IL-6 in blood plasma was increased to higher degree and at statistically significant difference, up to 32.9±2.3 pg/mL versus 6.5±0.7 pg/mL in the control group (p &lt; 0.001). Excessive content in the main group was also detected for IL-17 in blood plasma which was 25.4±1.9 pg/mL at the early post-COVID-19 period, whereas it was 7.8±0.7 pg/mL (p &lt; 0.001) in the age-matched patients with CHD only. TNFα and IFNγ levels were elevated among 60-74-year-old patients with CHD and COVID-19 at 3-4 weeks after recovery, being 128.6±2.7 pg/mL and 57.6±2.8 pg/mL, respectively. In control group, the concentration of these cytokines was significantly lower, i.e., 56.3±2.2 pg/mL and 25.9±1.7 pg/mL, respectively (p &lt; 0.001). The changes in contents of other cytokines studied seemed less pronounced, and the level of IL-4 was not significantly different between the both groups. Hence, in elderly patients with CHD and COVID-19 at 3-4 weeks after recovery, IL-6, IL-17, TNFα and IFNγ are the most elevated cytokines at the systemic level.

Oat bran prevents high-fat-diet induced muscular dysfunction, systemic inflammation and oxidative stress through reconstructing gut microbiome and circulating metabolome

Western-type diet characterized by high fat emerges a promoter of skeletal muscle dysfunctions. Oat bran was typically considered a healthy food of premium quality for its abundant dietary fiber. The present study comprehensively explored the effects of a diet rich in oat bran on skeletal muscle disfunctions in high-fat diet (HFD) fed mice. Dietary-fiber-rich oat bran significantly ameliorated HFD-induced skeletal muscle function abnormalities, as evidenced by a phenotype improvement in mice grip strength and endurance treadmill running distance, accompanied with the regulation of muscle functions related gene expressions, namely Fis1, Cytc, Mhy2 and Mhy4. Oat bran suppressed the production of systemic inflammatory cytokines while promoted superoxide dismutase and glutathione. Furthermore, oat bran significantly impacted gut microbiota composition by promoting short chain fatty acids (SCFAs) producers and certain probiotic genera, along with the enhancement of SCFAs. Oat bran also significantly decreased the circulating levels of inflammation-related metabolites and played roles in MAPK signaling, thereafter influencing skeletal muscle functions. Collectively, benefits from integration of biomedical indicators, microbiomics, and metabolomics demonstrates the benefits of oat bran consumption on prevention of HFD-related muscular dysfunctions via alleviating HFD-induced inflammation, gut dysbiosis, and systemic metabolism, pinpointing a novel mechanism underlying the muscle-promoting property of oat bran.

The herbicides glyphosate and glufosinate and the cyanotoxin β-N-methylamino-l-alanine induce long-term motor disorders following postnatal exposure: the importance of prior asymptomatic maternal inflammatory sensitization

BackgroundPrenatal maternal immune activation (MIA) and/or perinatal exposure to various xenobiotics have been identified as risk factors for neurological disorders, including neurodegenerative diseases. Epidemiological data suggest an association between early multi-exposures to various insults and neuropathologies. The “multiple-hit hypothesis” assumes that prenatal inflammation makes the brain more susceptible to subsequent exposure to several kinds of neurotoxins. To explore this hypothesis and its pathological consequences, a behavioral longitudinal procedure was performed after prenatal sensitization and postnatal exposure to low doses of pollutants.MethodsMaternal exposure to an acute immune challenge (first hit) was induced by an asymptomatic lipopolysaccharide (LPS) dose (0.008 mg/kg) in mice. This sensitization was followed by exposing the offspring to environmental chemicals (second hit) postnatally, by the oral route. The chemicals used were low doses of the cyanotoxin β-N-methylamino-l-alanine (BMAA; 50 mg/kg), the herbicide glufosinate ammonium (GLA; 0.2 mg/kg) or the pesticide glyphosate (GLY; 5 mg/kg). After assessing maternal parameters, a longitudinal behavioral assessment was carried out on the offspring in order to evaluate motor and emotional abilities in adolescence and adulthood.ResultsWe showed that the low LPS immune challenge was an asymptomatic MIA. Even though a significant increase in systemic pro-inflammatory cytokines was detected in the dams, no maternal behavioral defects were observed. In addition, as shown by rotarod assays and open field tests, this prenatal LPS administration alone did not show any behavioral disruption in offspring. Interestingly, our data showed that offspring subjected to both MIA and post-natal BMAA or GLA exposure displayed motor and anxiety behavioral impairments during adolescence and adulthood. However, this synergistic effect was not observed in the GLY-exposed offspring.ConclusionThese data demonstrated that prenatal and asymptomatic immune sensitization represents a priming effect to subsequent exposure to low doses of pollutants. These double hits act in synergy to induce motor neuron disease-related phenotypes in offspring. Thus, our data strongly emphasize that multiple exposures for developmental neurotoxicity regulatory assessment must be considered. This work paves the way for future studies aiming at deciphering cellular pathways involved in these sensitization processes.

Cytokine profile in the patients with combined cardio- and ophtalmopathies

Combined cardiological and ophthalmological pathology has a high prevalence in older age groups of the population and common pathogenetic mechanisms, among which, of course, is a violation of the cytokine profile. However, the cytokine profile of the blood was practically not analyzed in elderly patients with combined ischemic heart disease with glaucoma. The aim of the study was to study the cytokine profile in patients with combined cardio- and ophthalmopathology. The study was performed at the S.N. Fedorov National Medical Research Center “MNTK Eye Microsurgery”, in two groups: patients with combined coronary heart disease with glaucoma (n = 58 people), and patients with coronary heart disease (n = 49 people), who in both cases have the same age of 60-74 years. The diagnosis of glaucoma was carried out in accordance with the criteria of the “National Glaucoma Guidelines”. Electrocardiographic, echocardiographic, radiographic, and enzyme studies were performed to diagnose coronary heart disease. The determination of cytokines in blood plasma was carried out on the device “Becton Dickinson FACS Canto 2 (USA)” using a special set of CBA (BD Biosciences, USA). Among the patients of the compared groups of the same age, significant differences in most cytokines were revealed, namely, a predominant increase in patients with combined cardio- and ophthalmopathology relative to the group with coronary heart disease. The content of IL-5, IL-12, IFNγ, TNFα in the blood plasma of patients with coronary heart disease combined with glaucoma increased with a significant difference compared to patients with coronary heart disease. However, the highest increase among the cytokines under consideration is characteristic of IL-6 and IL-17, which amounted to 23.8±1.1 pg/mL and 20.2±1.7 pg/mL in patients with combined cardio- and ophthalmopathology versus 6.3±0.3 pg/mL and 7.9±0.5 pg/mL, respectively, in patients with coronary heart disease. At the same time, the level of IL-4 and IL-10 decreased significantly to 2.2±0.2 pg/mL and 6.4±0.4 pg/mL versus 4.8±0.3 pg/mL and 11.9±0.6 pg/mL. The use of logistic regression made it possible to determine the relative risk values of the studied blood cytokines and to develop uncorrected and adjusted models, according to which the closest association with the risk of developing combined coronary heart disease with glaucoma was established for IL-6 and IL-17, with the relative risk values in the uncorrected model of 2.87 and 2.71, respectively (p &lt; 0.001). However, in the adjusted model, the association of IL-6 with combined coronary heart disease with glaucoma increased to 2.92 (CI 2.80-3.27, p = 0.004), and IL-17 decreased to 2.64 (CI 2.51-2.85, p = 0.003). There was also a significant association of IL-4, IL-5, IL-12, IFNγ and TNFα with combined coronary heart disease with glaucoma. The study demonstrated new associations of systemic cytokines with the risk of developing combined coronary heart disease associated with glaucoma.

Pediatric autoinflammatory bone disorders-a mini review with special focus on pathogenesis and inborn errors of immunity.

Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms, Majeed syndrome and deficiency of the interleukin-1 receptor antagonist. These disorders result from innate immune system dysregulation and cytokine imbalance that triggers inflammasome activation causing downstream osteoclastogenesis and excessive bone remodeling. In this review, we will summarize the immunopathogenesis of pediatric autoinflammatory bone diseases with a special focus on the genetics and inborn errors of immunity, while briefly touching on the clinical manifestations and management of each disease as well as areas for future research.

Obesity in Pregnant Women and Its Impact on Maternal and Neonatal Morbidity

Obesity in pregnancy is currently a health problem that is associated with increased maternal and neonatal morbidity. Along with the times and lifestyles that are more modern, the incidence of obesity is also increasing. Clinically, obesity is defined as the condition of having excess adipose tissue. Obesity is related to insulin resistance and chronic inflammation. This makes obesity a risk factor for various non-contagious diseases such as cardiovascular disease, hypertension, diabetes mellitus, and cancer. The health consequences of maternal obesity are based on low-grade, chronic (meta-inflammatory) inflammation that occurs as a result of changes in the immune system and proinflammatory cytokines in maternal obesity and pregnancy. Obesity can have a negative impact on maternal, neonatal and labor outcomes. Several maternal complications that can occur due to obesity (BMI 30-34.9) and morbid obesity (BMI ≥ 35) are hypertension during pregnancy (10.2-12.3%), preeclampsia (3-6.3%), gestational diabetes (6.3-9.5%). Risks that can occur to the fetus, such as the occurrence of macrosomia (15.4-17.2%), preterm birth (4-5.5%) and impaired fetal growth (1-0.8%). Maternal obesity is also associated with an increased risk of neural tube defects (NTD) in babies, as well as a higher risk of abortion (1.70-3.11%). Obesity also has an impact on the delivery process. Mothers with obesity have a higher rate of vaginal operative procedures (8.5-11.1%), labor induction and longer duration of labor. The increase in caesarean section deliveries is caused by the occurrence of complications due to maternal obesity, namely the occurrence of preeclampsia, fetal distress, macrosomia, and induction failure.

Human mesenchymal stem-derived extracellular vesicles improve body growth and motor function following severe spinal cord injury in rat.

Spinal cord injury (SCI) in young adults leads to severe sensorimotor disabilities as well as slowing of growth. Systemic pro-inflammatory cytokines are associated with growth failure and muscle wasting. Here we investigated whether intravenous (IV) delivery of small extracellular vesicles (sEVs) derived from human mesenchymal stem/stromal cells (MSC) has therapeutic effects on body growth and motor recovery and can modulate inflammatory cytokines following severe SCI in young adult rats. Contusional SCI rats were randomized into three different treatment groups (human and rat MSC-sEVs and a PBS group) on day 7 post-SCI. Functional motor recovery and body growth were assessed weekly until day 70 post-SCI. Trafficking of sEVs after IV infusions in vivo, the uptake of sEVs in vitro, macrophage phenotype at the lesion and cytokine levels at the lesion, liver and systemic circulation were also evaluated. An IV delivery of both human and rat MSC-sEVs improved functional motor recovery after SCI and restored normal body growth in young adult SCI rats, indicating a broad therapeutic benefit of MSC-sEVs and a lack of species specificity for these effects. Human MSC-sEVs were selectively taken up by M2 macrophages in vivo and in vitro, consistent with our previous observations of rat MSC-sEV uptake. Furthermore, the infusion of human or rat MSC-sEVs resulted in an increase in the proportion of M2 macrophages and a decrease in the production of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 at the injury site, as well as a reduction in systemic serum levels of TNF-α and IL-6 and an increase in growth hormone receptors and IGF-1 levels in the liver. Both human and rat MSC-sEVs promote the recovery of body growth and motor function after SCI in young adult rats possibly via the cytokine modulation of growth-related hormonal pathways. Thus, MSC-sEVs affect both metabolic and neurological deficits in SCI.

An exploratory clinical trial on intra-lumbar injection of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.

2043 Background: No standard-of-care treatment was established for recurrent high-grade gliomas (rHGGs) yet. Intrathecal infusion of autologous chimeric antigen receptor-T (CAR-T) cells has displayed potent anti-tumor activity in one patient (Brown et al. N Engl J Med 2016). We evaluated the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of B7H3-specific allogeneic universal CAR-T (B7H3 UCAR-T) cells in patients with rHGGs. Methods: Eligible patients who had received standard treatment for newly-diagnosed high-grade gliomas but failed were treated with 2.5×107 B7H3 UCAR-T cells via intra-lumbar injection every month. Eligibility criteria included histologic and/or cytologic rHGGs, B7H3-positive antigen expression rate of &gt;50% in tumor tissue and Karnofsky performance status (KPS) ≥ 40. The primary endpoint was treatment-related adverse events (TAEs); secondary endpoints include overall survival (OS) and objective response rate (ORR); exploratory endpoints were PK and PD characteristics of B7H3 UCAR-T cells. Results: In the 7 patients enrolled, 4 (57.1%) were female, 5 (71.4%) glioblastoma (WHO Grade IV) and 2 (28.6%) diffuse midline glioma (WHO Grade IV), and the mean age was 40.4 years. The most common reported TAEs were increased cerebrospinal fluid (CSF) IL-6 (7/7, 100%), headache (7/7, 100%), increased blood IL-6 (6/7, 86%) and fever (6/7, 86%). No adverse events of grade 3 or greater related to B7H3 UCAR-T cells were reported. All the adverse events recovered or relieved after treatment. No typical or severe systemic cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GvHD) were observed during the study period. Based on Immunotherapy Response Assessment in Neuro-Oncology (iRANO), 3 of 7 patients had response to therapy (42.9%; 95% CI: 15.8 to 75.0) and 7 of 7 patients were stable disease (100%; 95% CI: 64.6 to 100). As of cutoff date (January 30, 2023), two patients died. The median OS was not reached (95% CI: 12.9 to could not be estimated). The median follow-up for OS was 15.6 months (95% CI: 14.7 to 16.1). OS rate at 12 months was 85.7% (95% CI: 48.7 to 97.4). The CAR DNA copy numbers increased 1 day after each administration and persist at least 1 month in cerebrospinal fluid. IL-6 concentrations in CSF and peripheral blood increased after each administration while the change and concentration values in peripheral blood were much lower than those in CSF. Conclusions: In patients with rHGGs, B7H3 UCAR-T cells was not associated with any toxic effects of grade 3 or higher. B7H3 UCAR-T cells resulted in a significantly longer overall survival and a higher objective response rate than history data. B7H3 UCAR-T cells persist well in patients. Clinical trial information: ChiCTR2100047968 .

Phase 1b clinical study of IRAK 1/4 inhibition for low-risk myelodysplastic syndromes refractory/resistant to prior therapies.

TPS7085 Background: Chronic stimulation of both interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to cause a bone marrow proinflammatory environment responsible for persistent cytopenia in patients with low-risk (LR)-MDS. IRAK1 and IRAK4 are serine/threonine kinases that are critical for the downstream signaling of IL-1R and most TLRs resulting in the production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis leading to bone marrow inflammation and cell death. Thus, IRAK1/4 inhibition is a potential target for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow allowing the restoration of hematopoiesis. R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. R835 is a potent and selective inhibitor of IRAK1 and IRAK4 kinases and inhibits TLR and IL-1R-dependent proinflammatory cytokine production in multiple cell types. In vivo, R835 blocks TLR4 and IL-1R-dependent systemic cytokine release in mice. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 healthy volunteer study (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the trial supported the advancement of R289 into further studies. An open-label Phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The current study (NCT05308264) includes a dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases will include patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria will include prior treatment for MDS that concluded &lt;4 weeks prior to study treatment. Dose Escalation Phase: Dose escalation will utilize a 3+3 design to determine the maximum tolerated dose (MTD). R289 tablets can be taken orally with or without food. Dose limiting toxicity (DLT) will be assessed at each dose level. The DLT evaluation period will be 28 days. After completion of the DLT evaluation period, patients who do not experience DLTs may remain on treatment at their respective dose level if they continue to demonstrate clinical benefit without toxicity. Dose Expansion Phase: Up to 10 additional patients with LR-MDS will be enrolled; the primary endpoint of the study will be the safety and tolerability of R289. The secondary endpoints will include an assessment of preliminary efficacy and characterization of the pharmacokinetics of R289. R289 will be administered to all patients at a dose not to exceed the MTD determined in the Dose Escalation Phase. The trial is currently recruiting at 8 US sites. Clinical trial information: NCT05308264 .

Adipocyte Na, K-ATPase Signaling Attenuates Experimental Uremic Cardiomyopathy.

Oxidative stress has been shown to cause an alteration of intracellular signaling in adipocytes that may lead to various comorbidities of obesity and cardiovascular complications. Evidence suggests that dysregulation of Na, K-ATPase signaling can contribute to systemic inflammation and redox signaling that leads to various metabolic disturbances. Hence the present study aims to explore the specific role of adipocyte Na, K-ATPase signaling in the amelioration of pathophysiological alterations of experimental uremic cardiomyopathy. Experimental uremic cardiomyopathy was induced by partial nephrectomy (PNx), and adipocyte-specific expression of NaKtide, a peptide that inhibits Na, K-ATPase signaling, was achieved using a lentivirus construct with NaKtide expression driven by an adiponectin promoter. Cardiomyopathy and anemia induced in partial nephrectomy mice were accompanied by an altered molecular phenotype of adipocytes, increased systemic inflammatory cytokines and oxidant stress within 4 weeks. These changes were significantly worsened by the addition of a Western diet (enriched in fat and fructose contents) but were prevented with specific expression of NaKtide in adipocytes. The skeletal muscle-specific expression of NaKtide did not ameliorate the disease phenotype. Adipocyte dysfunction and uremic cardiomyopathy developed in PNx mice, both were significantly ameliorated by the adipocyte-specific expression of NaKtide. These findings suggest that oxidative milieu in the adipocyte has a pivotal role in the development and progression of uremic cardiomyopathy in mice subjected to partial nephrectomy. If confirmed in humans, this may be a lead for future research to explore novel therapeutic targets in chronic renal failure.

Unraveling the Molecular and Cellular Pathogenesis of COVID-19-Associated Liver Injury.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) continues to cause substantial morbidity and mortality. Most infections are mild; however, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm, and acute respiratory distress syndrome. Patients with chronic liver disease have been frequently affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes may be a risk factor for disease progression, even in the absence of underlying liver disease. While the respiratory tract is a primary target of SARS-CoV-2, it has become evident that COVID-19 is a multisystemic infectious disease. The hepatobiliary system might be influenced during COVID-19 infection, ranging from a mild elevation of aminotransferases to the development of autoimmune hepatitis and secondary sclerosing cholangitis. Furthermore, the virus can promote existing chronic liver diseases to liver failure and activate the autoimmune liver disease. Whether the direct cytopathic effects of the virus, host reaction, hypoxia, drugs, vaccination, or all these risk factors cause liver injury has not been clarified to a large extent in COVID-19. This review article discussed the molecular and cellular mechanisms involved in the pathogenesis of SARS-CoV-2 virus-associated liver injury and highlighted the emerging role of liver sinusoidal epithelial cells (LSECs) in virus-related liver damage.

Patterns of cytokine release and association with new onset of post-cardiac surgery atrial fibrillation.

Postoperative Atrial Fibrillation (POAF) is a common complication of cardiac surgery, associated with increased mortality, stroke risk, cardiac failure and prolonged hospital stay. Our study aimed to assess the patterns of release of systemic cytokines in patients with and without POAF. A post-hoc analysis of the Remote Ischemic Preconditioning (RIPC) trial, including 121 patients (93 males and 28 females, mean age of 68 years old) who underwent isolated coronary artery bypass grafting (CABG) and aortic valve replacement (AVR). Mixed-effect models were used to analyze patterns of release of cytokines in POAF and non-AF patients. A logistic regression model was used to assess the effect of peak cytokine concentration (6 h after the aortic cross-clamp release) alongside other clinical predictors on the development of POAF. We found no significant difference in the patterns of release of IL-6 (p = 0.52), IL-10 (p = 0.39), IL-8 (p = 0.20) and TNF-α (p = 0.55) between POAF and non-AF patients. Also, we found no significant predictive value in peak concentrations of IL-6 (p = 0.2), IL-8 (p = >0.9), IL-10 (p = >0.9) and Tumour Necrosis Factor Alpha (TNF-α)(p = 0.6), however age and aortic cross-clamp time were significant predictors of POAF development across all models. Our study suggests no significant association exists between cytokine release patterns and the development of POAF. Age and Aortic Cross-clamp time were found to be significant predictors of POAF.

Renal denervation reverses ventricular structural and functional remodeling in failing rabbit hearts

Renal denervation (RDN) suppresses the activity of the renin–angiotensin–aldosterone system and inflammatory cytokines, leading to the prevention of cardiac remodeling. Limited studies have reported the effects of renal denervation on ventricular electrophysiology. We aimed to use optical mapping to evaluate the effect of RDN on ventricular structural and electrical remodeling in a tachycardia-induced cardiomyopathy rabbit model. Eighteen rabbits were randomized into 4 groups: sham control group (n = 5), renal denervation group receiving RDN (n = 5), heart failure group receiving rapid ventricular pacing for 1 month (n = 4), and RDN-heart failure group (n = 4). Rabbit hearts were harvested for optical mapping. Different cycle lengths were paced (400, 300, 250, 200, and 150 ms), and the results were analyzed. In optical mapping, the heart failure group had a significantly slower epicardial ventricular conduction velocity than the other three groups. The RDN-heart failure, sham control, and RDN groups had similar velocities. We then analyzed the 80% action potential duration at different pacing cycle lengths, which showed a shorter action potential duration as cycle length decreased (P for trend < 0.01), which was consistent across all groups. The heart failure group had a significantly longer action potential duration than the sham control and RDN groups. Action potential duration was shorter in the RDN-heart failure group than the heart failure group (P < 0.05). Reduction of conduction velocity and prolongation of action potential duration are significant hallmarks of heart failure, and RDN reverses these remodeling processes.

Persistent Neutrophil Infiltration and Unique Ocular Surface Microbiome Typify Dupilumab–Associated Conjunctivitis in Patients with Atopic Dermatitis

To elucidate the pathogenesis of dupilumab (Dupixent®)-associated ocular surface disease (DAOSD). Prospective single-center cohort study. Twenty patients with moderate-to-severe atopic dermatitis (AD) who received dupilumab and 10 age- and sex-matched healthy controls were enrolled in the study. The study cohort underwent a thorough slit-lamp and entire-body dermatologic examination. Conjunctival swabs and smears were collected at baseline, 4 and 16 weeks after treatment initiation, and during the conjunctivitis episode. To analyse the ocular surface microbiome, 16S ribosomal RNA sequencing was performed, smears were hematoxylin and eosin stained, and serum cytokines were measured by using a multiplex immunobead assay. Composition of ocular surface microbiome and cellular component as well as serum cytokine levels. Six of the 20 patients with AD developed DAOSD after dupilumab initiation; these patients responded after a delay to treatment as quantified by Eczema Area and Severity Index and Investigator's Global Assessment score. Conjunctival smears showed massive neutrophilic infiltration and serum analysis revealed increased systemic levels of neutrophil-priming proinflammatory cytokines, in particular interleukin-1β and tumor necrosis factor α, in patients with DAOSD compared with those without it. The ocular surface microbiome of patients with DAOSD was characterized by a diverse and persistent microbial colonization, particularly by Acetobacter aceti. In contrast, microbial diversity decreased in patients with AD without DAOSD after the initiation of dupilumab treatment, especially the abundance of Staphylococcus aureus. Invitro experiments substantiated the potential role of the microbiome, showing increased growth of A.aceti and decreased growth of S.aureus in presence of dupilumab. Persistent neutrophilic infiltration and a unique microbial landscape on the ocular surface associated with elevated levels of systemic proinflammatory cytokines typify DAOSD. Proprietary or commercial disclosure may be found after the references.

Lung infection by Pseudomonas aeruginosa induces neuroinflammation and blood–brain barrier dysfunction in mice

BackgroundSevere lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood–brain barrier (BBB) leakage and behavioral impairment.MethodsLung infection in mice was induced by instilling Pseudomonas aeruginosa (PA) intratracheally. We determined bacterial colonization in tissue, microvascular leakage, expression of cytokines and leukocyte infiltration into the brain.ResultsLung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell–cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 h and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b + CD45+ cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell–cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1β induced a significant reduction of barrier function coupled with tight junction (TJ) and adherens junction (AJ) diffusion and disorganization. Combined treatment with IL-1β and TNFα augmented the barrier injury.ConclusionsLung bacterial infection is associated with BBB disruption and behavioral changes, which are mediated by systemic cytokine release.