Changes In Inflammatory Markers Research Articles

Hemorheology and Inflammatory Marker Changes in Patients with Acute Ischemic Stroke after Intravenous Thrombolysis with Mechanical Thrombectomy.

To investigate hemorheology and inflammatory marker changes after treatment for acute ischemic stroke (AIS) using intravenous thrombolysis (IVT) with mechanical thrombectomy (MT). We retrospectively reviewed clinical records of patients with AIS (n=83) treated in The First Affiliated Hospital of Bengbu Medical College between January 2021 and December 2022 (n=83). The control group consisted of 38 patients who underwent IVT alone and the observation group consisted of 45 patients who underwent IVT with MT. We compared differences in mean variables related to hemorheology, inflammatory markers, and total efficacy between the two groups. We found that hemorheology values (plasma viscosity [PV], whole blood viscosity [WBV], fibrinogen [FIB], and hematocrit [HCT]), and the levels of inflammatory markers (tumor necrosis factor ɑ [TNF-ɑ] and interleukin-6 [IL-6]) were higher in the control group than in the observation group after treatment (P<0.05). In addition, the total efficacy of the observation group (93.3%) was higher than that in the control group (76.3%; P=0.016). The clinical efficacy of combined IVT and MT in the treatment of AIS is superior to IVT alone, improving levels of hemorheology and inflammatory markers in patients with AIS.

Investigation into changes in inflammatory and immune cell markers in pre-diabetic patients from Durban, South Africa

The prevalence of pre-diabetes is increasing in rapidly urbanizing cities, especially in individuals aged 25 − 45 years old. Studies also indicate that this condition is associated with aberrant immune responses that are also influenced by environmental factors. This study sought to investigate changes in the concentration of immune cells and select inflammatory markers in patients with pre-diabetes in Durban, South Africa. Blood samples collected from King Edward Hospital, after obtaining ethics approval, were divided into non-diabetic (ND), pre-diabetic (PD) and type 2 diabetic (T2D) using ADA criteria. In each sample, the concentration of immune cells and select inflammatory markers were determined. The results showed a significant increase in eosinophil and basophil levels in the PD group as compared to the ND group. Compared to ND, the PD and T2D groups had significant increases in serum TNFα, CD40L and fibrinogen concentrations. Additionally, there were decreases in serum CRP, IL-6, and P-selectin in the PD group while these markers increased in the T2D group. These findings were indicative of immune activation and highlight the impact of pre-diabetes in this population. More studies are recommended with a higher number of samples that are stratified by gender and represent the gender ratio in the city.

Subdiaphragmatic vagal nerve stimulation attenuates the development of hypertension and alters nucleus of the solitary tract transcriptional networks in the spontaneously hypertensive rat.

Augmented vagal signaling may be therapeutic in hypertension. Most studies to date have used stimulation of the cervical vagal branches. Here, we investigated the effects of chronic intermittent electric stimulation of the ventral subdiaphragmatic vagal nerve branch (sdVNS) on long-term blood pressure, immune markers, and gut microbiota in the spontaneously hypertensive rat (SHR), a rodent model of hypertension characterized by vagal dysfunction, gut dysbiosis, and low-grade inflammation. We evaluated the effects of sdVNS on transcriptional networks in the nucleus of the solitary tract (NTS), a major cardioregulatory brain region with direct gut vagal projections. Male juvenile SHRs were implanted with radiotelemetry transmitters and vagal nerve cuffs for chronic intermittent electric sdVNS, applied three times per day for 7 consecutive weeks followed by 1 wk of no stimulation. Blood pressure was measured once a week using telemetry in the sdVNS group as well as age-matched sham-stimulated SHR controls. At the endpoint, colonic and circulating inflammatory markers, corticosterone, and circulating catecholamines were investigated. Bacterial 16 s sequencing measured gut bacterial abundance and composition. RNA sequencing evaluated the effects of sdVNS on transcriptional networks in the NTS. SHRs that received sdVNS exhibited attenuated development of hypertension compared with sham animals. No changes in peripheral inflammatory markers, corticosterone, or catecholamines and no major differences in gut bacterial diversity and composition were observed following sdVNS, apart from decreased abundance of Defluviitaleaceale bacterium detected in sdVNS SHRs compared with sham animals. RNA sequencing revealed significant sdVNS-dependent modulation of select NTS transcriptional networks, including catecholaminergic and corticosteroid networks.NEW & NOTEWORTHY We show that stimulation of the ventral subdiaphragmatic vagal nerve branch may be a promising potential approach to treating hypertension. The data are especially encouraging given that rodents received only 30 min per day of intermittent stimulation therapy and in view of the potential of long-term blood pressure effects that are not stimulus-locked.

Updated Results of the Phase I BALLI-01 Trial of UCART22 Process 2 (P2), an Anti-CD22 Allogeneic CAR-T Cell Product Manufactured By Cellectis Biologics, in Patients with Relapsed or Refractory (R/R) CD22+ B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Introduction: UCART22 is a genetically modified allogeneic T-cell product manufactured from healthy donor cells. Donor-derived T-cells are transduced using a lentiviral vector to express the anti-CD22 chimeric antigen receptor (CAR) and are further modified using Cellectis' TALEN ® technology to disrupt the T-cell receptor alpha constant ( TRAC) and CD52 genes to minimize risk of graft-vs-host disease (GvHD) and allow use of an anti-CD52 antibody for lymphodepletion (LD). Preliminary results from patients treated with UCART22 manufactured by a CMO (Process 1 (P1)) showed that UCART22 was well-tolerated and meaningful responses were achieved at the highest dose level (DL 3; 5 x 10 6 cells/kg). The fludarabine, cyclophosphamide, and alemtuzumab (FCA) LD regimen was also shown to extend host lymphocyte suppression and improve UCART22 expansion versus fludarabine and cyclophosphamide (FC) alone (Boissel N, et al. EHA 2023). We now report updated results from the BALLI-01 study that includes the first patients treated with UCART22 Process 2 (P2) manufactured by Cellectis Biologics. Methods: The primary endpoints are safety, tolerability, and determining the MTD/RP2D of UCART22. Additional endpoints are anti-leukemic activity and expansion of UCART22. Eligibility criteria include age 15‒70y, B-ALL blast CD22 expression ≥ 70%, and ≥ 2 prior treatment regimens. After FCA (F 30 mg/m 2 × 3d, C 0.5g/m 2 × 3d, A 20 mg/d × 3d) LD regimen, pts received a single infusion of UCART22-P2. In vitro comparability assays suggested that UCART22 P2 was more potent than UCART22 P1, so dose escalation with UCART22 P2 started at DL2 (1 x 10 6 cells/kg) compared to the highest studied dose DL3 (5 x 10 6 cells/kg) with UCART22 P1. Results: As of 01 July 2023, 3 pts were enrolled into the first UCART22 P2 cohort at DL2. Pt 1 is a 17yo female with B-ALL with a hypodiploid karyotype and a germline TP53 mutation whose disease had previously failed to respond to multiagent chemotherapy, blinatumomab (blina), inotuzumab (ino), venetoclax (ven), allogeneic hematopoietic stem cell transplantation (HSCT), and autologous CD19 CAR T-cell therapy (CAR19) x2. Pt 2 is a 68yo female with Ph-negative B-ALL who relapsed with CD19-low disease after multiagent chemotherapy, ino, and blina. Pt 3 is a 27yo male with B-ALL with an ABL2 fusion who had failed multiagent chemotherapy, ino, blina, TKIs, and an experimental autologous CAR19. UCART22 P2 administered after the FCA LD regimen was well tolerated. No DLTs or ICANS were observed. Cytokine release syndrome (CRS) occurred in 2/3 (67%) pts, with one G1 that resolved without treatment and one G2 that resolved after tocilizumab x1. There was one G5 sepsis SAE at D40 considered related to UCART22 P2 and FCA LD in Pt 1. Responses were assessed beginning on D28. Up to FC/FCA-DL3 with 18 pts treated with UCART22 P1, 1 CR, 4 CRi, and 2 morphologic leukemia-free states (MLFS) were observed, with 3 responses occurring out of 6 (50%) patients treated with FCA-DL3 (previously reported, EHA 2023). For UCART22 P2, FCA-DL2, 2/3 pts (67%) responded: Pt 2 achieved an MRD neg CR lasting over 84 days after UCART22 infusion; Pt 1 achieved an MRD negative MLFS up to D40. Pt 3 was refractory to treatment, however this pt received bridging therapy with dasatinib for his ABL2 fusion, and on Day -1, only 47% of the leukemic cells expressed CD22 (down from 88% at screening). UCART22 P2 expansion was observed by flow cytometry in peripheral blood with peak of 79 cells/μl in Pt 1 and 225 cells/μl in Pt 2, both at D11, with predominantly CD8 cells expanding. Inflammatory markers such as ferritin, IFN-γ, TNF-α and IL-6 levels increased more than 3-fold, correlating with UCART22 P2 expansion and CRS. Summary : In vitro comparability studies indicated that UCART22 P2 was more potent than UCART22 P1, and this was suggested clinically, as there was a 67% response rate at DL2 with UCART22 P2 compared to 50% at DL3 with UCART22 P1. Use of UCART22 P2 did not lead to any grade ≥3 CRS, and no DLTs or ICANS was observed. UCART22 P2 expansion was seen in the two responders, which closely correlated with CRS and changes in inflammatory markers. These data support the safety and preliminary efficacy of UCART22 P2 in this poor-risk R/R B-ALL population. The study continues to enroll pts treated with UCART22 P2 at dose level 2i (2.5 x 10 6 cells/kg), and updated data will be presented.

Clinical Outcomes of Patients with Hematologic Malignancies Receiving Bendamustine Lymphodepletion Prior to CAR-T Cell Infusion

CAR-T cell therapy has revolutionized the treatment of adult patients with relapsed/refractory (r/r) non-Hodgkin lymphomas (NHL) and multiple myeloma (MM). While lymphodepletion (LD) with fludarabine/cyclophosphamide (flu/cy) has been the standard, the fludarabine drug shortage has caused a shift toward the use of bendamustine as an alternative. This study expands upon previous investigations evaluating bendamustine as a LD agent prior to CART therapy. We conducted a retrospective study of 48 patients with r/r NHL (marginal zone lymphoma (MZL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL)) and MM who received bendamustine LD prior to treatment with commercial CART products at the UPMC Shadyside Hospital between 07/2022-04/2023. Data were collected using chart review and analyzed by descriptive statistics. Responses for NHL and MM were assessed based on the Lugano 2014 criteria and the International Myeloma Working Group consensus criteria, respectively. Toxicities were evaluated based on the American Society for Transplantation and Cellular Therapy consensus grading and the Common Terminology Criteria for Adverse Events. 33 patients with NHL (24 with DLBCL, 2 with MZL, 2 with FL and 5 with MCL) and 15 with MM, were included with a mean age of 65.8 years. The median number of prior therapies was 2 [1 - 5] for NHL, and 5 [4 - 10] for MM. In the NHL cohort, 14/33 patients were treated in the second line. Among NHL patients, 5/33 patients received brexucabtagene autoleucel, 24/33 axicabtagene ciloleucel (axi-cel), and 4/33 lisocabtagene maraleucel (liso-cel). Among MM patients, 2/15 patients received idecabtagene vicleucel, and 13/15 ciltacabtagene autoleucel (cilta-cel). Grade (G) 1-2 CRS occurred in 23/33 of NHL and 14/15 of MM patients, without any reported G3 CRS. ICANS was reported in 9/33 (3 G3) of NHL and 7/15 (1 G3) of MM patients. The overall response rate (ORR) in MM patients was 12/15, with 6/12 achieving complete response (CR) or stringent CR (sCR) and 6/12 a very good partial response (VGPR), and only 1/12 progressing after a response. In the NHL cohort, we evaluated the ORR for every subtype. The ORR was 16/24 (11/16 CR and 5/16 PR) in DLBCL, 1/2 (CR) in MZL, 3/5 (all CR) in MCL, and 2/2 (all CR) in FL. Only 3 patients with DLBCL, 1 with MZL and 1 with MCL eventually progressed after a response. These response results are comparable with prior CART studies of flu/cy LD that have shown ORR range of 72-73% (CR 51-54%) for DLBCL ( Locke F, Lancet Oncol., 2019; Abramson JS, Lancet 2020), 91% (CR 60%) for FL ( Jacobsen CA, Lancel Oncol. 2022), and 98% (sCR 78%) for MM ( Berdeja JG, Lancet 2021). Next, we evaluated the change in hematologic parameters after LD. Absolute lymphocyte counts (ALC) showed mean decreases of 66.8% (± 28.4%) in NHL and 69.3% (± 16.4%) in MM from pre-LD to the day of CAR-T infusion (D CART), with median time-to-nadir (TTN) post-D CART of 1 [0-13] days in NHL and 1 [0-8] days in MM. We then compared the incidence of neutropenia in our cohort relative to historical controls treated with flu/cy LD. Neutropenia was seen in 80% of patients (G≥3, 68%) with axi-cel, 50% (G≥3, 50%) with liso-cel, and 100% (G≥3, 77%) with cilta-cel. This compares favorably to historical data with axi-cel, (86%; G≥3, 80%), liso-cel (63%; G≥3, 60%), and cilta-cel (96%; Gr≥3, 95%). Table 1 illustrates the grades of cytopenias and ANC nadir and TTN post-D CART in our study. Finally, we investigated the mean change in inflammatory markers as a surrogate of CAR-T activation and expansion. CRP showed a median increase of 2.8-fold [0 - 66.5] in a median of 5 [0-55] days in NHL, and a median increase of 4.6-fold [0.22 - 74.9] in a median of 8 [2-15] days in MM. Ferritin had a median increase of 1.2-fold [0- 50] in median of 9 [0-171] days in NHL, and median increase of 3.8-fold [0.63 - 59.4] in median 10 [0-148] days in MM. In conclusion, bendamustine is a successful LD agent prior to CAR-T infusion, yielding response rates comparable to historical controls in NHL and MM. Notably, our study reveals a favorable safety profile with a lower rate of high grade cytopenias than was seen in the pivotal trials using flu/cy LD. These findings are reassuring regarding the use of bendamustine as an alternative LD agent in the face of the ongoing fludarabine drug shortage. Further studies assessing CART copy numbers and persistence of CART are needed.

Exploratory Study on Impact of Comorbid Sleep Apnea Treatment in Patients with Polycythemia Vera and Essential Thrombocythemia

Background: Systemic inflammation has been implicated in the progression of myeloproliferative neoplasms (MPNs), polycythemia vera (PV) and essential thrombocythemia (ET). Obstructive sleep apnea (OSA) is a highly prevalent disorder that can lead to TNF-driven systemic inflammation. OSA leads to oxidative stress and NF-kB driven inflammatory gene expression through the mechanistic pathways of intermittent hypoxia and autonomic activation. We therefore sought to understand the prevalence of OSA in patients with MPNs and the feasibility of understanding the impact of treating comorbid sleep apnea in patients with PV and ET. Methods: Patients with PV and ET diagnosed using the 2008 or 2016 WHO criteria underwent STOP-BANG questionnaires to evaluate for the likelihood of OSA. Based on the finding of 3 or more positive responses on STOP-BANG questionnaire (PLoS One 2015;10:e0143697), patients underwent further evaluation with polysomnography or home sleep apnea test to diagnose OSA at an American Academy of Sleep Medicine-certified sleep laboratory (Figure 1). Patients with apnea-hypopnea index (AHI) of 5 or more events per hour and Eastern Cooperative Oncology Group scale score of 0-2 underwent continuous positive airway pressure therapy (CPAP). Effects of CPAP therapy on MPN-symptom assessment form total symptom scores (MPN-SAF TSS), JAK2V617F, MPL and CALR allelic burden, and exploratory endpoints of changes in inflammatory and thrombotic markers were ascertained (Figure 1). Comparisons with observational cohorts were planned to ascertain changes in the above endpoints at 0-, 3- and 6-months intervals (Figure 1). Based on a 40% reduction in allele burden (SD of 25%) and correlation of 0.5 between paired measurements, it was estimated that using a paired t-test with 27 evaluable patients will provide a 95% power to detect a 20% change in JAK2V617F burden from 40% to 20%. Similarly, assuming a 50% correlation (SD of 16) between pre- and post-therapy MPN-SAF TSS scores, 27 evaluable patients will provide a 80% power to detect a change of 10 at the two-sided 0.025 significance level. Results: Screening for OSA in patients with ET and PV revealed a high prevalence of OSA risk based on STOP-BANG scores. 26/29 males (mean age 63.6±11.8 years; BMI 29±3.3) and 16/26 females (mean age 61.5±12.8 years; BMI 28.2±6.5) had STOP-BANG scores of 3 or more. 8 patients with PV and ET have so far been enrolled into this study. 6/8 patients (age ranges from 41-74 years; 4 females and 2 males) with OSA (AHI 5-56 events/hr; 4% oxygen desaturation index 4.7-30/hr) underwent CPAP therapy. 1/6 patients in the CPAP arm did not tolerate CPAP and was excluded. 5/6 patients completed study procedures as did 2 additional patients without OSA in the observational study arm. Of 5/6 patients undertaking CPAP, 3/5 had the JAK2V617F mutations whereas 2/5 had the CALR mutation. JAK2V617F allele burdens at baseline in 2/5 patients were 80.7% and 4% at baseline and reduced to 73% and 1% at 6 months respectively whereas the third patient had undetectable JAK2V617F burdens throughout the study. All except one patient experienced improvement in MPN-SAF TSS scores after 6 months of CPAP therapy. While all 5 patients treated with CPAP showed improvements in C-reactive protein levels, analysis of NFkB1, TNF and IL-6 transcript levels showed mixed results. Similar mixed results were found with hypoxia-inducible factor (HIF) target gene expression ( SLC2A1, VEGF-A, EDN1) and markers of iron turnover (% transferrin saturation, transferrin, iron and ferritin levels) despite reduction in erythropoietin values in 4/5 patients with CPAP therapy at 6 months. Conclusions: Given the significant likelihood of OSA in patients with PV and ET (as based on STOP-BANG scores of 3 or more), there is need to evaluate and treat for OSA. Preliminary results show abnormalities in inflammatory markers with reductions in C-reactive protein and erythropoietin levels following CPAP therapy even though mixed results were noted in inflammatory and HIF-target gene transcripts, and markers of iron turnover. Larger studies and longer follow-up are required to understand the impact of OSA on not only the thrombotic and inflammatory milieu in patients with MPNs, but also the benefit of treating on prevention of disease progression and thrombotic manifestations common in MPNs. Funding: Huntsman Interventional Trial Grant CTO #HCI-17-HEM 28.

Supplementation with postbiotic from Bifidobacterium Breve BB091109 improves inflammatory status and endocrine function in healthy females: a randomized, double-blind, placebo-controlled, parallel-groups study

This study evaluated the effects of dietary supplementation with a postbiotic extract of Bifidobacterium breve BB091109 on pro-inflammatory cytokines levels and markers of endocrine function. A prospective, double-blind, placebo-controlled, randomized, single-centered, parallel study was conducted on a group of 40–55-year-old females. The study included 30 healthy females, divided into two groups: a supplement (n = 20) and a placebo (n = 10) groups. Blood and saliva samples were collected at baseline (wk0), after 4 weeks (wk 4) and 12 weeks (12wk) of daily supplementation (500 mg), and 4 weeks (wk 16) after termination of supplementation. The levels of fasting CRP, IL-6, IL-10, TNF-α, IFN-γ, DHEA, estradiol, estriol, progesterone, cortisol and human growth hormone were analysed. The results revealed a significant effect of the 90-day supplementation with B. breve postbiotic extract on changes in CRP, IL-6 levels, DHEA, estradiol and estriol. In conclusion, the supplementation with the B. breve postbiotic extract improved endocrine function in females over 40 years old and induced protective changes in inflammatory markers. These findings highlight the potential health benefits of this supplementation in promoting hormonal balance and reducing inflammation in this population.

Impact of anti-tumor necrosis factor treatment on lipid profiles in Korean patients with ankylosing spondylitis.

To investigate the effects of anti-tumor necrosis factor (TNF) treatment on lipid profiles and identify risk factors for an increase in total cholesterol (TC) after the anti-TNF treatment in ankylosing spondylitis (AS) patients. This retrospective cohort study analyzed AS patients who received the first-line anti-TNF treatment. Patients with at least nine months of follow-up were included; those who were under 18 years or on any lipid-lowering agent were excluded. A linear mixed model was used to assess the impact of anti-TNF inhibitors on disease activity and lipid profile (TC, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TG]). Univariable and multivariable linear regression were used to identify risk factors for an increase in TC after 3 months of anti-TNF treatment. A total of 315 AS patients were enrolled (78.1% male, median age 32.0 [26.0~41.0]). TC, HDL, and TG levels significantly increased particularly within the first 3 months of anti-TNF treatment, while LDL level did not show significant changes. Changes in inflammatory markers and lipid particles (TC, LDL, TG) were correlated over time, but HDL showed no significant correlation. Older age, higher baseline erythrocyte sedimentation rate, and lower baseline LDL level were related to an increase in TC after 3 months of the anti-TNF treatment. In AS patients, anti-TNF treatment has been found to increase lipid particles, potentially due to its anti-inflammatory effects. Future research should explore the underlying mechanism and the clinical implications of dyslipidemia, particularly the occurrence of cardiovascular events, following anti-TNF treatment in AS patients.

Hydrogen gas and the gut microbiota are potential biomarkers for the development of experimental colitis in mice.

Inflammatory bowel disease (IBD) is a chronic disease characterised by repeated relapses and remissions and a high recurrence rate even after symptom resolution. The primary method for IBD diagnosis is endoscopy; however, this method is expensive, invasive, and cumbersome to use serially. Therefore, more convenient and non-invasive methods for IBD diagnosis are needed. In this study, we aimed to identify biological gas markers for the development of gut inflammation. Using dextran sulphate sodium (DSS)-induced colitis mouse models, five biological gases were analysed to identify predictive markers for the development of gut inflammation. Additionally, the correlation between the changes in gas composition, gut microbiota, and inflammatory markers was assessed. The hydrogen (H2) level was found to be negatively correlated with the level of lipocalin-2 (LCN2), a gut inflammation biomarker, and weight loss due to DSS-induced colitis. Furthermore, gut microbes belonging to the Rikenellaceae and Akkermansiaceae families were positively correlated with LCN2 levels and weight loss, whereas Tannerellaceae abundance was negatively correlated with LCN2 level and weight loss and positively correlated with H2 levels. This study provides new insights for IBD diagnosis; the H2 levels in biological gases are a potential biomarker for intestinal inflammation, and specific gut microbes are associated with H2 level changes.

Beneficial effects of recombinant CER-001 high-density lipoprotein infusion in sepsis: results from a bench to bedside translational research project.

Sepsis is characterized by a dysregulated immune response and metabolic alterations, including decreased high-density lipoprotein cholesterol (HDL-C) levels. HDL exhibits beneficial properties, such as lipopolysaccharides (LPS) scavenging, exerting anti-inflammatory effects and providing endothelial protection. We investigated the effects of CER-001, an engineered HDL-mimetic, in a swine model of LPS-induced acute kidney injury (AKI) and a Phase 2a clinical trial, aiming to better understand its molecular basis in systemic inflammation and renal function. We carried out a translational approach to study the effects of HDL administration on sepsis. Sterile systemic inflammation was induced in pigs by LPS infusion. Animals were randomized into LPS (n = 6), CER20 (single dose of CER-001 20mg/kg; n = 6), and CER20 × 2 (two doses of CER-001 20mg/kg; n = 6) groups. Survival rate, endothelial dysfunction biomarkers, pro-inflammatory mediators, LPS, and apolipoprotein A-I (ApoA-I) levels were assessed. Renal and liver histology and biochemistry were analyzed. Subsequently, we performed an open-label, randomized, dose-ranging (Phase 2a) study included 20 patients with sepsis due to intra-abdominal infection or urosepsis, randomized into Group A (conventional treatment, n = 5), Group B (CER-001 5mg/kg BID, n = 5), Group C (CER-001 10mg/kg BID, n = 5), and Group D (CER-001 20mg/kg BID, n = 5). Primary outcomes were safety and efficacy in preventing AKI onset and severity; secondary outcomes include changes in inflammatory and endothelial dysfunction markers. CER-001 increased median survival, reduced inflammatory mediators, complement activation, and endothelial dysfunction in endotoxemic pigs. It enhanced LPS elimination through the bile and preserved liver and renal parenchyma. In the clinical study, CER-001 was well-tolerated with no serious adverse events related to study treatment. Rapid ApoA-I normalization was associated with enhanced LPS removal and immunomodulation with improvement of clinical outcomes, independently of the type and gravity of the sepsis. CER-001-treated patients had reduced risk for the onset and progression to severe AKI (stage 2 or 3) and, in a subset of critically ill patients, a reduced need for organ support and shorter ICU length of stay. CER-001 shows promise as a therapeutic strategy for sepsis management, improving outcomes and mitigating inflammation and organ damage. The study was approved by the Agenzia Italiana del Farmaco (AIFA) and by the Local Ethic Committee (N° EUDRACT 2020-004202-60, Protocol CER-001- SEP_AKI_01) and was added to the EU Clinical Trials Register on January 13, 2021.

Association of Dynamic Changes in Illness Severity Scores Biochemical and Inflammatory Markers with Outcomes in Invasively Ventilated COVID-19 in Resource-limited Settings: A Time-course Study

Association of Dynamic Changes in Illness Severity Scores Biochemical and Inflammatory Markers with Outcomes in Invasively Ventilated COVID-19 in Resource-limited Settings: A Time-course Study

ANXA1sp attenuates sepsis-induced myocardial injury by promoting mitochondrial biosynthesis and inhibiting oxidative stress and autophagy via SIRT3 upregulation.

Sepsis-induced myocardial injury is one of the most difficult complications of sepsis in intensive care units. Annexin A1 (ANXA1) short peptide (ANXA1sp) protects organs during the perioperative period. However, the protective effect of ANXA1sp against sepsis-induced myocardial injury remains unclear. We aimed to explore the protective effects and mechanisms of ANXA1sp against sepsis-induced myocardial injury both in vitro and in vivo. Cellular and animal models of myocardial injury in sepsis were established with lipopolysaccharide. The cardiac function of mice was assessed by high-frequency echocardiography. Elisa assay detected changes in inflammatory mediators and markers of myocardial injury. Western blotting detected autophagy and mitochondrial biosynthesis-related proteins. Autophagic flux changes were observed by confocal microscopy, and autophagosomes were evaluated by TEM. ATP, SOD, ROS, and MDA levels were also detected.ANXA1sp pretreatment enhanced the 7-day survival rate, improved cardiac function, and reduced TNF-α, IL-6, IL-1β, CK-MB, cTnI, and LDH levels. ANXA1sp significantly increased the expression of sirtuin-3 (SIRT3), mitochondrial biosynthesis-related proteins peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), and mitochondrial transcription factor A (TFAM). ANXA1sp increased mitochondrial membrane potential (△Ψm), ATP, and SOD, and decreased ROS, autophagy flux, the production of autophagosomes per unit area, and MDA levels. The protective effect of ANXA1sp decreased significantly after SIRT3 silencing in vitro and in vivo, indicating that the key factor in ANXA1sp's protective role is the upregulation of SIRT3. In summary, ANXA1sp attenuated sepsis-induced myocardial injury by upregulating SIRT3 to promote mitochondrial biosynthesis and inhibit oxidative stress and autophagy.

The Protective Pathways Activated in Kidneys of αMUPA Transgenic Mice Following Ischemia\Reperfusion-Induced Acute Kidney Injury.

Despite the high prevalence of acute kidney injury (AKI), the therapeutic approaches for AKI are disappointing. This deficiency stems from the poor understanding of the pathogenesis of AKI. Recent studies demonstrate that αMUPA, alpha murine urokinase-type plasminogen activator (uPA) transgenic mice, display a cardioprotective pathway following myocardial ischemia. We hypothesize that these mice also possess protective renal pathways. Male and female αMUPA mice and their wild type were subjected to 30 min of bilateral ischemic AKI. Blood samples and kidneys were harvested 48 h following AKI for biomarkers of kidney function, renal injury, inflammatory response, and intracellular pathways sensing or responding to AKI. αMUPA mice, especially females, exhibited attenuated renal damage in response to AKI, as was evident from lower SCr and BUN, normal renal histology, and attenuated expression of NGAL and KIM-1. Notably, αMUPA females did not show a significant change in renal inflammatory and fibrotic markers following AKI as compared with wild-type (WT) mice and αMUPA males. Moreover, αMUPA female mice exhibited the lowest levels of renal apoptotic and autophagy markers during normal conditions and following AKI. αMUPA mice, especially the females, showed remarkable expression of PGC1α and eNOS following AKI. Furthermore, MUPA mice showed a significant elevation in renal leptin expression before and following AKI. Pretreatment of αMUPA with leptin-neutralizing antibodies prior to AKI abolished their resistance to AKI. Collectively, the kidneys of αMUPA mice, especially those of females, are less susceptible to ischemic I/R injury compared to WT mice, and this is due to nephroprotective actions mediated by the upregulation of leptin, eNOS, ACE2, and PGC1α along with impaired inflammatory, fibrotic, and autophagy processes.

Use of Remdesivir in Patients Hospitalized for COVID-19 Pneumonia: Effect on the Hypoxic and Inflammatory State.

Remdesivir is one of the most attractive options for patients with hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). The aim of our study was to evaluate the effect of remdesivir on the hypoxic and inflammatory state in patients with moderate to severe COVID-19. We retrospectively enrolled 112 patients admitted for COVID-19 pneumonia, requiring low-flow oxygen, 57 treated with remdesivir plus standard of care (SoC) and 55 treated only with SoC that were similar for demographic and clinical data. We evaluated changes in hypoxemia and inflammatory markers at admission (Day 0) and after 5 days of treatment (Day 5) and the clinical course of the disease. From Day 0 to Day 5, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F) increased from 222 ± 62 to 274 ± 97 (p < 0.0001) in the remdesivir group and decreased from 223 ± 62 to 183 ± 76 (p < 0.05) in the SoC group. Interleukine-6 levels decreased in the remdesivir (45.9 to 17.5 pg/mL, p < 0.05) but not in the SoC group. Remdesivir reduced the need for ventilatory support and the length of hospitalization. In conclusion, compared to standard care, remdesivir rapidly improves hypoxia and inflammation, causing a better course of the disease in moderate to severe COVID-19.

48h Normothermic Machine Perfusion With Urine Recirculation for Discarded Human Kidney Grafts.

Normothermic machine perfusion (NMP) has reshaped organ preservation in recent years. In this preclinical study, prolonged normothermic perfusions of discarded human kidney grafts were performed in order to investigate perfusion dynamics and identify potential quality and assessment indicators. Five human discarded kidney grafts were perfused normothermically (37°C) for 48h using the Kidney Assist device with a red-blood-cell based perfusate with urine recirculation. Perfusion dynamics, perfusate and urine composition as well as injury markers were measured and analyzed. Donor age ranged from 41 to 68years. All but one kidney were from brain dead donors. Perfusions were performed successfully for 48h with all discarded kidneys. Median arterial flow ranged from 405 to 841mL/min. All kidneys excreted urine until the end of perfusion (median 0.43mL/min at the end of perfusion). While sodium levels were consistently lower in urine compared to perfusate samples, this was only seen for chloride and potassium in kidney KTX 2. Lactate, AST, LDH as well as pro-inflammatory cytokines increased over time, especially in kidneys KTX 3 and 4. Ex vivo normothermic perfusion is able to identify patterns of perfusion, biological function, and changes in inflammatory markers in heterogenous discarded kidney grafts.

Association of urinary bisphenols with oxidative stress and inflammatory markers and their role in obesity

Bisphenol A (BPA) and its substitutes are widely used in daily life. Animal and cell line experiments have confirmed the effects of bisphenols on oxidative stress and inflammation. However, current population evidence for the effects of BPA alternatives, such as bisphenol F (BPF) and bisphenol S (BPS), on oxidative stress and inflammation is still sparse. Based on the National Health and Nutrition Examination Survey 2013–2016 data, our study used linear regression, weighted quantile sum model, and Bayesian kernel machine regression model to evaluate the effects of BPA, BPS, and BPF alone and in combination on oxidative stress (serum total bilirubin, and iron) and inflammation (alkaline phosphatase, C-reactive protein, γ-glutamyl transferase ferritin, neutrophil count, lymphocyte count, and neutrophil-to-lymphocyte ratio) markers. On this basis, the possible roles of oxidative stress and inflammation in obesity, which is associated with exposure to bisphenols (BPs), were initially explored. Based on the different covariates selected, a total of 3039 and 2258 participants were included in our study for models 1 and 2, respectively; the median age of participants was 48 years, and 48.7 % were male. Based on all models, our results showed that exposure to BPs alone or in combination was associated with downregulation of serum total bilirubin. Urinary BPF concentration was specifically associated with the neutrophil-to-lymphocyte ratio. Serum total bilirubin may play a role in the association between obesity and BP mixture exposure. Upregulation of the neutrophil-to-lymphocyte ratio was not associated with obesity. In conclusion, our study found that single or combined exposure to BPs, as measured in urine, may be associated with changes in oxidative stress and inflammatory markers, and a decrease in serum total bilirubin may play a mediating role in BP-induced obesity.

Modulation of the Cardiovascular Effects of Polycyclic Aromatic Hydrocarbons: Physical Exercise as a Protective Strategy.

Exposure to polycyclic aromatic hydrocarbons (PAHs) present in air pollution increases cardiovascular risk. On the contrary, physical exercise is a widely used therapeutic approach to mitigate cardiovascular risk, but its efficacy in an environment of air pollution, particularly with PAHs, remains unclear. This study investigates the effects of exercise on inflammation, endothelial dysfunction, and REDOX imbalance due to PAH exposure using a mouse model. Twenty male BALB/c mice were subjected to a mixture of PAHs (phenanthrene, fluoranthene, pyrene) in conjunction with aerobic exercise. The investigation evaluated serum levels of inflammatory cytokines, gene expression linked to inflammatory markers, endothelial dysfunction, and REDOX imbalance in aortic tissues. Furthermore, the study evaluated the expression of the ICAM-1 and VCAM-1 proteins. Exercise led to notable changes in serum inflammatory cytokines, as well as the modulation of genes associated with endothelial dysfunction and REDOX imbalance in aortic tissue. In turn, exercise produced a modulation in the protein expression of ICAM-1 and VCAM-1. The findings implicate the potential of exercise to counter PAH-induced damage, as demonstrated by changes in markers. In conclusion, exercise could mitigate the adverse effects related to exposure to PAHs present in air pollution, as evidenced by changes in inflammatory markers, endothelial dysfunction, and REDOX imbalance.

Skeletal muscle adaptations in patients with lung cancer: Longitudinal observations from the whole body to cellular level.

Cancer and its treatment can adversely affect skeletal muscle, impacting physical function, treatment response and survival. No studies, however, have comprehensively characterized these muscle adaptations longitudinally in human patients at the cellular level. We examined skeletal muscle size and function from the whole body to the sub-cellular level in 11 patients with non-small cell lung cancer (NSCLC; 6 male/5 female, mean age 58±3years) studied over a 2-month observation period starting during their first cycle of standard of care cancer treatment and in 11 age- and sex-matched healthy controls (HC) without a current or past history of cancer. Biopsies of the vastus lateralis were performed to assess muscle fibre size, contractility and mitochondrial content, along with assessments of physical function, whole muscle size and function, and circulating cytokines. Body weight, composition and thigh muscle area and density were unaltered over time in patients with NSCLC, while muscle density was lower in patients with NSCLC versus HC (P=0.03). Skeletal muscle fibre size decreased by 18% over time in patients (all P=0.02) and was lower than HC (P=0.02). Mitochondrial fractional area and density did not change over time in patients, but fractional area was lower in patients with NSCLC compared with HC (subsarcolemmal, P=0.04; intermyofibrillar, P=0.03). Patients with NSCLC had higher plasma concentrations of IL-6 (HC 1.40±0.50; NSCLC 4.71±4.22; P<0.01), GDF-15 (HC 569±166; NSCLC 2071±1168; P<0.01) and IL-8/CXCL8 (HC 4.9±1.8; NSCLC 10.1±6.0; P=0.02) compared with HC, but there were no changes in inflammatory markers in patients with NSCLC over time. No changes were observed in markers of satellite cell activation or DNA damage in patients and no group differences were noted with HC. Whole-muscle strength was preserved over time in patients with NSCLC coincident with improved single fibre contractility. This study is the first to comprehensively examine longitudinal alterations in skeletal muscle fibre size and function in patients with NSCLC and suggests that muscle fibre atrophy occurs during cancer treatment despite weight stability and no changes in conventional clinical measurements of whole body or thigh muscle size over this period.

N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic trial

BackgroundIn the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence.Objectives and methodsAn open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS).ResultsPrior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces TH1, TH17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points.ConclusionsOral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc’s potential to control residual brain inflammation, myelin repair and neurodegeneration in MS.

EVALUATION OF INFLAMMATORY MARKERS IN CRITICALLY ILL ICU PATIENTS WITH AND WITHOUT ACUTE KIDNEY INJURY

Objective: Acute Kidney Injury (AKI) is a prevalent condition among patients admitted to the intensive care unit (ICU), with high incidence and increased mortality rates. AKI often induces the elevation of inflammatory biomarkers used for diagnosing infection. This study aimed to investigate changes in inflammatory markers in the setting of AKI.&#x0D; Methods: This retrospective study included patients admitted to the ICUs of Burdur State Hospital between January 2019 and January 2023. Data from 958 patients were analyzed, and AKI was classified by the Acute Kidney Injury Network (AKIN) criteria. Only creatinine data were used as information on urine output was not available. The cohort was stratified into following groups: no AKI (AKI 0), b) creatine levels between 1.60 and 2.50 mg/dL (AKI I), creatine levels between 2.51 and 3.99 mg/dL (AKI II), and creatine levels above 4 and receiving renal replacement therapy (AKI III).&#x0D; Results: Of the 958 patients, male and female distribution was 55.1% (n= 528) and 44.9% (n= 430) respectively. The median age of the study cohort was 79 years (IQR=18.3 years). Neutrophil-to-lymphocyte ratio, procalcitonin, and C-reactive protein levels were found to increase significantly in direct relation to the severity of AKI (p