Molecules In Patients Research Articles

Effect of tacrolimus on soluble costimulatory molecules in patients with refractory myasthenia gravis

ObjectivesTo investigate the expression and possible role of soluble costimulatory molecules in the treatment of refractory myasthenia gravis. MethodsThirty-two patients with refractory myasthenia gravis were enrolled into this study and given tacrolimus 3 mg/day. At the beginning of treatment and 12 months follow-up period, clinical data were collected and recorded. The clinical classification of myasthenia gravis Foundation (MGFA) was performed. The MGFA-quantitative myasthenia gravis score (MGFA-QMGS), manual muscle test (MMT), MG activity of daily living (MG-ADL) and the activity of daily living (MG-ADL), the 15-item myasthenia gravis quality of life (MG QOL-15) and the dose change of prednisone were used to evaluate the efficacy. The expression levels of soluble costimulatory molecules and their ligands (sPD-1/sPD-L1, sICOS/sICOSL, sCD40/sCD40L), soluble CD25 and IL-2 in serum were determined by enzyme-linked immunosorbent assay (ELISA). ResultsWe observed that oral administration of 3 mg tacrolimus daily for 1 year can significantly improve the clinical symptoms of patients with refractory myasthenia gravis, which is characterized by a significant reduction in clinical scores, such as QMG, MMT, ADL, MGQOL-15, and a reduction daily oral prednisolone (PSL) dose (P < 0.0001).We also found that the levels of plasma sPD-1, sCD40, IL-2 in refractory MG patients increased significantly, and those decreased significantly 12 months after tacrolimus treatment (P < 0.05). The level of sCD25 was negatively correlated with clinical severity scores (P < 0.05). After tacrolimus treatment, the level of sPD-L1 increased although there was no significant difference. ConclusionTacrolimus could relieve the symptoms of refractory MG and significantly decrease the levels of plasma sPD-1, sICOSL, sCD40, sCD25 and IL-2. Soluble costimulatory molecules might be potential biomarkers for MG and tacrolimus treatment.

Correlation between Expression of CD47 Molecule in Patients with Newly Diagnosed Adult Acute Myeloid Leukemia and Clinical Prognosis

To investigate the expression of CD47 molecules in patients with newly diagnosis of adult acute myeloid leukemia (AML) and its correlation with clinical prognosis. 20 patients with acute myeloid leukemia diagnosed in Shanghai Fengxian District Central hospital from April 2020 to October 2021 and 5 cases with non malignant hematological diseases in the control group were collected, and the expression of CD47 in single nuclear cells of bone marrow and peripheral blood was detected by real-time fluorescence quantitative polymerase chain reaction (qPCR). Combined with the blood image, bone marrow smears, flow cytometry, chromosome and gene detection, ECOG score, etc. during the patient's initial diagnosis, the relationship between the patient's prognosis and CD47 was evaluated. The expression of CD47 in bone marrow (P=0.0115) and peripheral blood mononuclear cells (P=0.0069) in new diagnosis AML patients was significantly higher than that of controls. In bone marrow mononuclear cells, the total survival time of patients with high CD47 expression was less than that of CD47 low expression patients (P=0.036). There was statistical significance in difference stratification group (P=0.012), but there was no statistical significance between CD47 expression and survival time in peripheral blood mononuclear cells (P=0.116). There were no statistical significance between bone marrow mononuclear cell CD47 expression and gene mutation fusion genes related to leukemia , CD34+, CD38+, CD123+ (P>0.05). The proportion of bone marrow protocells in AML patients was >50%, the ECOG score was >2 points, MLLELL fusion gene and chromosome prognosis stratification were all risk factors affecting the survival of patients (P=0023, 0.036, 0.012, 0.001, respectively). The high expression of bone marrow CD47 in AML patients indicated a high risk of recurrence (P=0.017). The high expression of bone marrow mononuclear cell CD47 in AML patients indicates poorer survival and higher risk of recurrence.

Correlation Analysis of miR-1246 Expression in Saliva of Patients with Chronic Periodontitis and Periodontal Indexes, Inflammatory Cytokines, and Protease Molecules.

Objective The study aimed to investigate the correlation of miR-1246 in saliva with periodontal indicators, inflammatory cytokines, and protease molecules in patients with chronic periodontitis. Methods Thirty-five patients with chronic periodontitis were included as the chronic periodontitis group, and 35 healthy individuals were selected as the healthy control group during the same period. The miR-1246 levels, inflammatory cytokine interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor-α (TNF-α), matrix metalloproteinase (MMP-1), MMP-8, and MMP tissue inhibitor (TIMP-1) in saliva were determined, and periodontal indexes, including the plaque index (PLI), bleeding index (BI), periodontal probing depth (PD), and attachment loss (AL) were examined. Results The salivary levels of miR-1246, IL-1β, IL-6, IL-17, TNF-α, MMP-1, MMP-8, and TIMP-1 and the periodontal indexes PLI, GI, PD, and AL in the chronic periodontitis group were significantly higher than those in the healthy control (P < 0.05). Salivary levels of miR-1246 in patients with chronic periodontitis were positively correlated with the levels of IL-1β, IL-6, IL-17, TNF-α, MMP-1, MMP-8, TIMP-1, PLI, GI, PD, and AL (P < 0.05). Conclusion Abnormally elevated levels of miR-1246 in saliva of patients with chronic periodontitis correlate with levels of periodontal indices, inflammatory cytokines, and protease molecules.

Evidence-Based Commentary: Testing and Treating Latent Tuberculosis Before Starting Biologics and Small Molecules in Patients with Inflammatory Bowel Disease

Evidence-Based Commentary: Testing and Treating Latent Tuberculosis Before Starting Biologics and Small Molecules in Patients with Inflammatory Bowel Disease

Single-Cell RNA Sequencing of Peripheral Blood Mononuclear Cells From Acute Myocardial Infarction.

BackgroundAcute myocardial infarction (AMI) can occur in patients with atherosclerotic disease, with or without plaque rupture. Previous studies have indicated a set of immune responses to plaque rupture. However, the specific circulating immune cell subsets that mediate inflammatory plaque rupture remain elusive.MethodsTen AMI patients were enrolled in our study (five with and five without plaque rupture; plaque characteristics were identified by optical coherence tomography). By single-cell RNA sequencing, we analyzed the transcriptomic profile of peripheral blood mononuclear cells.ResultsWe identified 27 cell clusters among 82,550 cells, including monocytes, T cells, NK cells, B cells, megakaryocytes, and CD34+ cells. Classical and non-classical monocytes constitute the major inflammatory cell types, and pro-inflammatory genes such as CCL5, TLR7, and CX3CR1 were significantly upregulated in patients with plaque rupture, while the neutrophil activation and degranulation genes FPR2, MMP9, and CLEC4D were significantly expressed in the intermediate monocytes derived from patients without plaque rupture. We also found that CD4+ effector T cells may contribute to plaque rupture by producing a range of cytokines and inflammatory-related chemokines, while CD8+ effector T cells express more effector molecules in patients without plaque rupture, such as GZMB, GNLY, and PRF1, which may contribute to the progress of plaque erosion. Additionally, NK and B cells played a significant role in activating inflammatory cells and promoting chemokine production in the plaque rupture. Cell–cell communication elaborated characteristics in signaling pathways dominated by inflammatory activation of classical monocytes in patients with plaque rupture.ConclusionsOur studies demonstrate that the circulating immune cells of patients with plaque rupture exhibit highly pro-inflammatory characteristics, while plaque erosion is mainly associated with intermediate monocyte amplification, neutrophil activation, and degranulation. These findings may provide novel targets for the precise treatment of patients with AMI.

Average molecular weight levels in patients with myocardial infarction against COPD depending on presence of complications in acute period

Purpose. To study the levels of average molecules in patients with myocardial infarction against the background of chronic obstructive disease depending on the presence of complications in the acute period of the infarction.Materials and methods. We studied 225 patients with STEMI. In 195 of them the MI developed against the background of COPD, and in 130 of them it was mono-inflammatory. Among mono-nososologic patients there were 85 patients with acute MI without any complications and 45 patients with complications. Among patients with COPD, 62 patients had uncomplicated MI, and 133 had complicated MI. The comparison group consisted of 110 somatically healthy individuals. Average molecules were determined according to M. Ya. Malakhova (1995) method by direct spectrometry. Statistical data processing was performed using SPSS 26.0 software package.Results of the study. The levels of LMWP and OP in various biological fluids in patients with complicated MI were statistically significantly higher both among patients with MI as a mononosomal disease and in the presence of COPD. Patients with complications registered higher levels of catabolic pool, endogenous intoxication index and lower values of intoxication coefficient. Among MI patients without complications stage I of endogenous intoxication prevailed, and among the patients with complicated MI and with uncomplicated MI against COPD – stage II, and among the patients with complicated MI against COPD – stage III.Conclusion. Complicated myocardial infarction is characterized by more pronounced endogenous intoxication. In comorbid patients with complicated MI, endogenous intoxication is more pronounced than in complicated MI without COPD. The demonstrability of the LMWP and OP levels allows us to recommend their use in prognostic algorithms for the development of coronary pathology in comorbid patients.

MO643: Haemoperfusion Combined with Standard Haemodialysis May Have a Beneficial Effect on Serum Beta-2 Microglobulin Levels in Chronic Haemodialysis Patients

Abstract BACKGROUND AND AIMS Standard haemodialysis (HD) with low-flux membranes does not provide adequate middle molecular weight (MMW) clearance of uraemic toxins [1] and on-line haemodiafiltration (OL-HDF) may not be easily applicable and cost effective in some centres. We investigated whether low-flux conventional HD combined with hemoperfusion (HP) may offer any benefit regarding serum beta-2 microglobulin (β2M) levels as a surrogate of middle molecules in patients haemodialyzed for many years and we compared the method-combination with OL-HDF. METHOD We studied 24 stable anuric patients during 6 months, under standard medical therapy, aged 69 years (46–90), M: F = 20:4, on chronic HD for 84 (65–286) months, who formed three groups: A (GrA), B (GrB) and C (GrC). Each group included 8 age- and HD vintage-matched patients respectively. In GrA patients, a type HA130 cartridge for HP was connected in parallel to the low-flux polysulfone dialyzer and this combination of standard HD with HP (HD + HP) was used once a week for the first month, once every 2 weeks for the second month and once a month for the next 4 months. GrB patients underwent only standard HD treatment with low-flux polysulfone membranes and GrC patients were treated with OL-HDF. In all three groups serum β2M levels were determined at months 0 (M0) and 6 (M6), before (pre-dialysis, preD) and after (post-dialysis, postD) the second weekly session. RESULTS Serum preD β2M levels ​​were similar in GrA and GrB at M0 (44.1 ± 8.6 versus 34.6 ± 16.2 mg/L; P = NS) and at M6 (46.1 ± 7.6 versus 41.1 ± 18.9 mg/L; P = NS). In GrC, preD-β2M values were lower compared with GrA at both M0 (31.1 ± 4.2 mg/L; P = .008) and M6 (33.8 ± 6.82 mg/L; P = .02). In GrC, serum postD-β2M levels ​​decreased significantly at both M0 (7.4 ± 1.9 mg/L; P &amp;lt; .001) and M6 (9.9 ± 3.8 mg/L; P&amp;lt;.001). The postD reduction was maintained, with no difference between M0 and M6. An improvement/decrease in β2M values ​was observed only in GrA between M0 and M6 (−5.8 ± 7.2 versus 1.8 ± 5mg/L; P = .03) but not in GBr. CONCLUSION OL-HDF is obviously the most effective method for elimination of MMW uraemic toxins and in particular β2M [2–3]. Interestingly, the combination HD + HP seems to be more effective than low-flux HD alone [4] and it could be useful for specific patient cases in daily clinical practice in order to prevent or delay the onset and deterioration of symptomatic amyloidosis. Possible result improvement with a more frequent use of HD + HP needs further investigation.

Neoadjuvant Chemoradiotherapy Changes the Landscape of Soluble Immune Checkpoint Molecules in Patients With Locally Advanced Rectal Cancer.

BackgroundWe aimed to investigate clinical implications of specific soluble immune checkpoint molecules (sICMs) in locally advanced rectal cancer (LARC) patients treated with neoadjuvant chemoradiotherapy (nCRT).MethodsWe prospectively enrolled 30 LARC patients treated with nCRT and collected blood samples from them before, during, and after nCRT for prospective studies. Immune checkpoints often refer to T cell surface molecules influencing the immune response. Immune checkpoints, in the form of a soluble monomeric form, is widely present in blood. In the study, eight immune checkpoint-related plasma proteins, including programmed death-ligand 1 (PD-L1), CD80, CD86, CD28, CD27, glucocorticoid-induced tumor necrosis factor receptor (GITR), GITR ligand (GITRL), and inducible T-cell costimulator (ICOS), were measured using the Luminex platform. Two independent pathologists categorized patients as the good responders and the poor responders according to Dworak tumor regression grade (TRG).ResultsOf the 30 patients, the levels of sPD-L1, sCD80, sCD86, sCD28, sGITR, sGITRL, sCD27, and sICOS decreased during nCRT (Pre-nCRT vs. During-nCRT, all p<0.05) but were restored after nCRT treatment (Pre-nCRT vs. Post-nCRT, all p>0.05). In the 14 good responders, the levels of sICMs, other than sGITR (p=0.081) and sGITRL (p=0.071), decreased significantly during nCRT (Pre-nCRT vs. During-nCRT, p<0.05), but they were all significantly increased after nCRT (During-nCRT vs. Post-nCRT, all p<0.05). In the 16 poor responders, only sCD80 was significantly reduced during nCRT (Pre-nCRT vs. During-nCRT, p<0.05), and none was significantly increased after nCRT (During-nCRT vs. Post-nCRT, all p<0.05). High levels of sICMs before nCRT were associated with poor response (all OR≥1). The Pre-model that incorporated the 8 sICMs before nCRT yielded a good predictive value (AUC, 0.848) and was identified as an independent predictor of treatment response (OR, 2.62; 95% CI, 1.11-6.18; p=0.027).ConclusionOur results suggest chemoradiotherapy could influence the change of sPD-L1, sCD80, sCD86, sCD28, sGITR, sGITRL, sCD27, and sICOS in patients with LARC. The levels of the majority of soluble immune checkpoint molecules were reduced during nCRT and then restored at the end of nCRT, particularly in patients who responded well to nCRT. Combined baseline sICMs can be developed to predict treatment response.

Potential Molecular Biomarkers of Central Nervous System Damage in Breast Cancer Survivors.

Damage of the central nervous system (CNS), manifested by cognitive impairment, occurs in 80% of women with breast cancer (BC) as a complication of surgical treatment and radiochemotherapy. In this study, the levels of ICAM-1, PECAM-1, NSE, and anti-NR-2 antibodies which are associated with the damage of the CNS and the endothelium were measured in the blood by ELISA as potential biomarkers that might reflect pathogenetic mechanisms in these patients. A total of 102 patients enrolled in this single-center trial were divided into four groups: (1) 26 patients after breast cancer treatment, (2) 21 patients with chronic brain ischemia (CBI) and asymptomatic carotid stenosis (ICA stenosis) (CBI + ICA stenosis), (3) 35 patients with CBI but without asymptomatic carotid stenosis, and (4) 20 healthy female volunteers (control group). Intergroup analysis demonstrated that in the group of patients following BC treatment there was a significant increase of ICAM-1 (mean difference: −368.56, 95% CI −450.30 to −286.69, p < 0.001) and PECAM-1 (mean difference: −47.75, 95% CI −68.73 to −26.77, p < 0.001) molecules, as compared to the group of healthy volunteers. Additionally, a decrease of anti-NR-2 antibodies (mean difference: 0.89, 95% CI 0.41 to 1.48, p < 0.001) was detected. The intergroup comparison revealed comparable levels of ICAM-1 (mean difference: −33.58, 95% CI −58.10 to 125.26, p = 0.76), PECAM-1 (mean difference: −5.03, 95% CI −29.93 to 19.87, p = 0.95), as well as anti-NR-2 antibodies (mean difference: −0.05, 95% CI −0.26 to 0.16, p = 0.93) in patients after BC treatment and in patients with CBI + ICA stenosis. The NSE level in the group CBI + ICA stenosis was significantly higher than in women following BC treatment (mean difference: −43.64, 95% CI 3.31 to −83.99, p = 0.03). Comparable levels of ICAM-1 were also detected in patients after BC treatment and in the group of CBI (mean difference: −21.28, 95% CI −111.03 to 68.48, p = 0.92). The level of PECAM-1 molecules in patients after BC treatment was also comparable to group of CBI (mean difference: −13.68, 95% CI −35.51 to 8.15, p = 0.35). In conclusion, among other mechanisms, endothelial dysfunction might play a role in the damage of the CNS in breast cancer survivors.

IOIBD Recommendations for Clinical Trials in Ulcerative Proctitis: The PROCTRIAL Consensus

Clinical trials evaluating biologics and small molecules in patients with ulcerative colitis are predominantly excluding ulcerative proctitis. The objective of the Definition and endpoints for ulcerative PROCtitis in clinical TRIALs initiative was to develop consensus statements for definitions, inclusion criteria, and endpoints for the evaluation of ulcerative proctitis in adults. Thirty-five international experts held a consensus meeting to define ulcerative proctitis, and the endpoints to use in clinical trials. Based on a systematic review of the literature, statements were generated, discussed, and approved by the working group participants using a modified Delphi method. Consensus was defined as at least 75% agreement among voters. The group agreed that the diagnosis of ulcerative proctitis should be made by ileocolonoscopy and confirmed by histopathology, with the exclusion of infections, drug-induced causes, radiation, trauma, and Crohn's disease. Ulcerative proctitis was defined as macroscopic extent of lesions limited to 15 cm distance from the anal verge in adults. Primary and secondary endpoints were identified to capture response of ulcerative proctitis to therapy. A combined clinical and endoscopic primary endpoint for the evaluation of ulcerative proctitis disease activity was proposed. Secondary endpoints that should be evaluated include endoscopic remission, histologic remission, mucosal healing, histologic endoscopic mucosal improvement, disability, fecal incontinence, urgency, constipation, and health-related quality of life. In response to the need for guidance on the design of clinical trials in patients with ulcerative proctitis, the Definition and end points for ulcerative PROCtitis in clinical TRIALs consensus provides recommendations on the definition and endpoints for ulcerative proctitis clinical trials.

Impact of metabolic disorders on endometrial receptivity in patients with polycystic ovary syndrome.

The present study investigated the expression of endometrial receptivity-related molecules in patients with polycystic ovary syndrome (PCOS) and different androgen status, insulin resistance (IR) levels, and body mass indexes (BMI) to identify the mechanism underlying their effects on pregnancy outcomes. The present study recruited 43 participants from November 2020 to January 2021, which were classified into five groups: i) Hyperandrogenemia (HA) combined with impaired glucose tolerance group (n=8); ii) HA combined with diabetes mellitus group (n=8); iii) HA combined with non-IR (NIR) group (n=10); iv) non-HA (NHA) androgen combined with IR group (n=8); and v) NHA combined with NIR group (n=9). In addition, according to their BMIs, patients were sub-grouped into lean/normal (n=27), overweight (n=8) or obese (n=8) groups. The mRNA expression levels of endometrial receptivity-related molecules were detected using reverse transcription-quantitative PCR. In addition, flow cytometry was used to determine the phenotype and percentage of uterine natural killer cells (uNK). According to the results, patients with PCOS and IR status, HA and obesity (BMI ≥24 kg/m2) demonstrated significantly decreased mRNA expression levels of adiponectin, adiponectin receptor (AdipoR)1, AdipoR2, adapter protein containing PH domain, PTB domain and leucine zipper motif 1, estrogen receptor (ER) α, ERβ, progesterone receptor (PR), IL-15, integrin β3 avβ3, and insulin-like growth factor binding protein-1, but increased mRNA expression levels of IL-6 and IL-8 compared with NHA + NIR group or lean/normal group, respectively. In addition, obese patients with PCOS demonstrated increased mRNA expression levels of PR compared with overweight patients. This suggested that insulin resistant status, HA, and obesity could alter the endometrial receptivity of patients with PCOS, which may explain poorer embryo implantation and pregnancy outcomes in clinics.

The Effects of Mannuronic Acid on IL-1β, IL-17A, STAT1, and STAT3 Gene Expressions and TLR2 and TLR4 Molecules in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic neurologic disease defined by inflammation and demyelination of the central nervous system that comes with variable degrees of axonal and neuronal damage. The efficacy of β-D-mannuronic acid (M2000) as a novel drug with immunosuppressive properties (patented: PCT/EP2017/067920), has been shown in an experimental model of MS. In this study, the effects of M2000 on interleukin (IL)-1β, IL-17A, signal transducer and activator of transcription (STAT) 1, and STAT3 gene expressions and Toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4) molecules in patients with secondary progressive MS were evaluated. In this study, 14 patients with secondary progressive MS and 14 healthy subjects (as control group) were entered from the phase 2 clinical trial (Clinical Trial identifier, IRCT2016111313739N6). The gene expressions of IL-1β, IL-17A, STAT1, and STAT3 were assessed at the baseline and then measured after 6months of therapy with M2000 by using the quantitative real-time polymerase chain reaction method. Moreover, the expressions of TLR2 and TLR4 molecules on peripheral blood mononuclear cells were evaluated by the flow cytometry method. The gene expressions of IL-17A, STAT1, and STAT3 in patients with MS decreased after 6months of therapy with M2000 comparing before treatment. Also, the gene expression of IL-1β decreased numerically after 6months. Furthermore, the expressions of TLR2 and TLR4 on PBMCs of the patients declined when compared to baseline. The results of this investigation revealed that M2000 could downregulate IL-17, STAT1, and STAT3 genes in patients with secondary progressive MS and also reduce the expressions of TLR2 and TLR4 on PBMCs. Moreover, M2000 declined numerically IL-β gene expression.

Single-cell RNA-seq reveals altered NK cell subsets and reduced levels of cytotoxic molecules in patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is an autoimmune disease with unknown aetiology. To unravel the mechanisms mediating AS pathogenesis, we profiled peripheral blood mononuclear cells (PBMCs) from AS patients and healthy subjects using 10X single‐cell RNA sequencing. The frequencies of immune cell subsets were evaluated by flow cytometry. NK cells were purified from PBMCs using isolation kit and were examined for gene expression by RT‐qPCR. Plasma levels of cytolytic molecules were examined by enzyme‐linked immunosorbent assay. Compared to healthy controls, AS patients showed a significant decrease in total NK cells as well as CD56dim NK subset, whereas CD56bright NK cells were increased. Additionally, impaired expression of cytotoxic genes in NK cells of AS patients was observed by bioinformatics algorithm and verified by RT‐qPCR and flow cytometry. Consistent with changes in transcriptomics, we found decreased plasma levels of granzymes, but not granulysin, in AS patients. Furthermore, Pearson correlation analysis revealed a negative correlation between plasma GZMB levels and disease activity (r = −0.5275, p = 0.0358). No correlation was observed between plasma cytolytic molecules and biochemical indexes (ESR and CRP). Our findings uncover altered NK cell subsets and cytotoxic profiles in peripheral circulation of AS patients at single‐cell resolution.

Study of type 1 vascular adhesion molecules in patients with acute myocardial infarction with ST segment elevation at different body weights

Objective: to study the level of adhesion molecules in patients with STEMI with different BMI at the hospital stage and 12 months after the index event.Materials and methods: the study included 126 people with STEMI who had undergone PCI and 27 people in the control group. The analysis of the level of svcam‑1 in peripheral blood at the beginning of the disease and after 12 months was carried out, BMI and waist volume were measured. An assessment of the nature and frequency of complications after STEMI was performed.Results: the levels of biomarkers of the vascular endothelial adhesion molecule type 1 increase during the acute period of stemi, statistically signifi tly decrease, but remain increased by 3.5 times 12 months after the index event compared with the initial values. There was no association of VCAM‑1 with visceral obesity in the groups of our patients. Vascular endothelial adhesion molecules of type 1 increase in patients with a fatal outcome, as well as with an increase in the severity of OSN and CHF. Thus, VCAM 1 can be a predictor of an unfavorable outcome of AMI.Conclusions: the article presents the study of a marker of systemic inflammation VCAM‑11 in patients with STEMI with various types of obesity or BMI at the stage of hospitalization and outpatient follow‑up during the year. The determination of the VCAM‑1 level can be used to assess the intensity of the inflammatory process and the risk of adverse outcomes.

Effects of Continuous Positive Airway Pressure on Cell Adhesion Molecules in Patients with Obstructive Sleep Apnea: A Meta-Analysis.

Previous studies have confirmed that patients with obstructive sleep apnea (OSA) have higher systemic inflammatory markers, including intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1(VCAM-1), and E-selectin compared to control subjects. However, the effects of continuous positive airway pressure (CPAP) therapy on circulating levels of ICAM-1, VCAM-1, and E-selectin in OSA patients remain inconsistent. Therefore, the primary purpose of the present meta-analysis is to estimate the effect of CPAP therapy on these cell adhesion molecules (CAMs) in patients with OSA. The PubMed, Scopus, Embase, and Cochrane Library databases were searched. The overall effects were measured by the standardized mean difference (SMD) with a 95% confidence interval (CI). A random effects model or a fixed-effects model was used, depending on the heterogeneity of the studies. A total of 11 studies were included, comprising 650 OSA patients. The pooled results showed that CPAP therapy significantly decreased ICAM-1 (SMD = - 0.283, 95% CI - 0.464 to - 0.101, p = 0.002) and E-selectin levels (SMD = - 0.349, 95% CI - 0.566 to - 0.133, p = 0.002). In contrast, there was no significant improvement of VCAM-1 levels after CPAP treatment (SMD = - 0.160, 95% CI - 0.641 to 0.320, p = 0.513). Our meta-analysis demonstrated that CPAP treatment significantly decreased the circulating levels of ICAM-1 and E-selectin in OSA patients. Thus, ICAM-1 and E-selectin may be effective markers to evaluate CPAP therapy for reducing OSA cardiovascular risk in clinical practice.

Robust T-Cell Responses in Anti-CD20-Treated Patients Following COVID-19 Vaccination: A Prospective Cohort Study.

BackgroundPatients treated with anti-CD20 therapy are particularly at risk of developing severe COVID-19, however little is known regarding COVID-19 vaccine effectiveness in this population.MethodsThis prospective observational cohort study assesses humoral and T-cell responses after vaccination with 2 doses of mRNA-based COVID-19 vaccines in patients treated with rituximab for rheumatic diseases or ocrelizumab for multiple sclerosis (n=37), compared to immunocompetent individuals (n=22).ResultsSARS-CoV-2-specific antibodies were detectable in only 69.4% of patients and at levels that were significantly lower compared to controls who all seroconverted. In contrast to antibodies, Spike (S)-specific CD4+ T cells were equally detected in immunocompetent and anti-CD20 treated patients (85-90%) and mostly of a Th1 phenotype. Response rates of S-specific CD8 + T cells were higher in ocrelizumab (96.2%) and rituximab-treated patients (81.8%) as compared to controls (66.7%). S-specific CD4 + and CD8 + T cells were polyfunctional but expressed more activation markers in patients than in controls. During follow-up, three MS patients without SARS-CoV-2-specific antibody response had a mild breakthrough infection. One of them had no detectable S-specific T cells after vaccination.ConclusionsOur study suggests that patients on anti-CD20 treatment are able to mount potent T-cell responses to mRNA COVID-19 vaccines, despite impaired humoral responses. This could play an important role in the reduction of complications of severe COVID-19.

Third-Generation Chimeric Antigen Receptor (CAR) T Cells in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL) - Results from the Heidelberg Trial 1 (HD-CAR-1 trial)

IntroductionChimeric antigen receptor (CAR) T cell (CART) therapy has shown to be a new and very promising therapeutical method in patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). The investigator-initiated Heidelberg-CAR-T-cell-trial 1 (HD-CAR-1) evaluates both efficacy and safety of escalating doses of 3 rd-generation CD19-directed CARTs comprising CD28 and 4-1BB as costimulatory molecules in patients with r/r ALL and NHL. Leukapheresis, manufacturing, administration, patient monitoring and follow-up were all conducted in-house at the Heidelberg University Hospital.MethodsTreatment was conducted with escalating doses of autologous 3 rd-generation CARTs after lymphodepletion with fludarabine (90 mg/m 2) and cyclophosphamide (1,500 mg/m 2) in patients with r/r acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or Non-Hodgkin's lymphoma (NHL), with subtype including diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL) or mantle cell lymphoma (MCL). Treatment efficacy as well as occurrence of toxicities, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections or cytopenia, were evaluated. Following prior results regarding dose-dependent efficacy and excellent toxicity profile with dose levels (DL) I, II and III (10 6, 5×10 6 and 20×10 6 CARTs/m 2), a trial amendment was approved for treatment of patients with higher CART doses (DL IV, V and VI: 5x10 7, 10x10 7 and 20x10 7 CARTs/m 2).ResultsOverall, screening was performed for 32 patients. Two patients were considered screening failures due to rapidly progressive disease (PD) and uncontrolled hepatitis B infection, respectively; leading to 30 patients enrolled in the study. The HD-CAR-1 product was given to 27 patients (12 patients with ALL, four with CLL, four with MCL, five with DLBCL, and two with FL) in different dose levels (six patients with DL I, six patients with DL II, eight patients with DL III, 5 patients with DL IV, 2 patient with DL V). The CART product was not given to two patients due to PD and lethal septic complication, respectively. Severe CAR-T toxicity was rare, as only two patients developed CRS ≥ III°. Both patients received treatment with tocilizumab, while one was additionally treated with steroids. No ICANS ≥ III° were reported in the study.54% of patients achieved a complete response (CR) with an overall response rate (ORR) of treated patients of 65%. In a subgroup response analysis, an ORR of 92% (83% CRs) with 50% of all patients achieving MRD-negative CR was seen in ALL patients. In the NHL/CLL cohort, an ORR of 43% and a CR rate of 29% were observed. Figure 1 displays OS and PFS results till the end of study (EOS, day +90).ConclusionAcademic CART production was feasible for all enrolled patients. Patients responded clinically to treatment and CARTs displayed a highly favorable safety profile. Overall, HD-CAR-1 accounts for clinical evaluation of 3 rd generation CARTs. [Display omitted] DisclosuresSchubert: Gilead: Consultancy. Schmitt: TolerogenixX Ltd: Current Employment; Hexal: Other: Travel grant; Jazz Pharmaceuticals: Other: Travel grant; Therakos/Mallinckrodt: Research Funding. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Dreger: Riemser: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy; BMS: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; Roche: Consultancy, Speakers Bureau. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; TolerogenixX: Current holder of individual stocks in a privately-held company; Kite Gilead: Other: Travel grants; Bluebird Bio: Other: Travel grants; Novartis: Other: Travel grants, Research Funding; Hexal: Other: Travel grants, Research Funding; Apogenix: Research Funding.

Profound differences in IgE and IgG recognition of micro-arrayed allergens in hyper-IgE syndromes.

BackgroundThe specificities of IgE and IgG for allergen molecules in patients with inborn errors of immunity (IEI) have not been investigated in detail.ObjectiveTo study IgE and IgG antibody specificities in patients with defined hyper‐IgE syndromes (HIES) using a comprehensive panel of allergen molecules.MethodsWe used chips containing micro‐arrayed allergen molecules to analyze allergen‐specific IgE and IgG levels in sera from two groups of HIES patients: Autosomal recessive mutations in phosphoglucomutase‐3 (PGM3); Autosomal dominant negative mutations of STAT3 (STAT3); and age‐matched subjects with allergic sensitizations. Assays with rat basophil leukemia cells transfected with human FcεRI were performed to study the biological relevance of IgE sensitizations.ResultsMedian total IgE levels were significantly lower in the sensitized control group (212.9 kU/L) as compared to PGM3 (5042 kU/L) and STAT3 patients (2561 kU/L). However, PGM3 patients had significantly higher allergen‐specific IgE levels and were sensitized to a larger number of allergen molecules as compared to STAT3 patients. Biological relevance of IgE sensitization was confirmed for PGM3 patients by basophil activation testing. PGM3 patients showed significantly lower cumulative allergen‐specific IgG responses in particular to milk and egg allergens as compared to STAT3 patients and sensitized controls whereas total IgG levels were comparable to STAT3 patients and significantly higher than in controls.ConclusionThe analysis with multiple micro‐arrayed allergen molecules reveals profound differences of allergen‐specific IgE and IgG recognition in PGM3 and STAT3 patients which may be useful for classification of IEI and clinical characterization of patients.

Efficacy of structurally modifying molecules in patients with degenerative-dystrophic spine pathology

Efficacy of structurally modifying molecules in patients with degenerative-dystrophic spine pathology

Safety and efficacy of combining biologics or small molecules for inflammatory bowel disease or immune-mediated inflammatory diseases: A European retrospective observational study.

Background and aimsFew data are available regarding the combination of biologics or small molecules in inflammatory bowel disease (IBD) patients. We report safety and efficacy of such combinations through a retrospective multicentre series.MethodsCombination therapy was defined as the concomitant use of two biologics or one biologic with a small molecule. Patient demographics, disease characteristics and types of combinations were recorded. Safety was evaluated according to the occurrence of serious infection, opportunistic infection, hospitalisation, life‐threatening event, worsening of IBD or immune‐mediated inflammatory diseases (IMID), cancer and death. Efficacy was evaluated as the physician global assessment of the combination and comparison of clinical/endoscopic scores of IBD/IMID activity prior and during combination.ResultsA total of 104 combinations were collected in 98 patients. Concomitant IMID were present in 41 patients. Reasons for starting combination therapy were active IBD (67%), active IMID or extra‐intestinal manifestations (EIM) (22%), both (10%) and unclassified in 1. Median duration of combination was 8 months (interquartile range 5–16). During 122 patient‐years of follow‐up, 42 significant adverse events were observed, mostly related to uncontrolled IBD. There were 10 significant infections, 1 skin cancer and no death. IBD disease activity was clinically improved in 70% and IMID/EIM activity in 81% of the patients. Overall, combination was continued in 55% of the patients.ConclusionsCombination of biologics and small molecules in patients with IBD and IMID/EIM seems to be a promising therapeutic strategy but is also associated with a risk of opportunistic infections or infections leading to hospitalisation in 10%.