Higher Serum Levels Research Articles

Differential cellular immune responses against Orientia tsutsugamushi Karp and Gilliam strains following acute infection in mice.

Scrub typhus is a leading cause of febrile illness in endemic countries due to infection with Orientia tsutsugamushi (Ot), a seriously understudied intracellular bacterium. Pulmonary involvement associated with vascular parasitism in patients is common and can develop into life threatening interstitial pneumonia. The diverse antigenicity of Ot genotypes and inter-strain differences in genome content are connected to varied virulence and clinical outcomes; however, detailed studies of strain-related pulmonary immune responses in human patients or small animal models of infection are lacking. In this study, we have used two clinically prevalent bacterial strains (Karp and Gilliam) to reveal cellular immune responses in inflamed lungs and potential biomarkers of disease severity. The results demonstrate that outbred CD-1 mice are highly susceptible to both Karp and Gilliam strains; however, C57BL/6 (B6) mice were susceptible to Karp, but resistant to Gilliam (with self-limiting infection), corresponding to their tissue bacterial burdens and lung pathological changes. Multicolor flow cytometric analyses of perfused B6 mouse lungs revealed robust and sustained influx and activation of innate immune cells (macrophages, neutrophils, and NK cells), followed by CD4+ and CD8+ T cells, during Karp infection, but such responses were greatly attenuated during Gilliam infection. The robust cellular responses in Karp-infected B6 mice positively correlated with significantly early and high levels of serum cytokine/chemokine protein levels (CXCL1, CCL2/3/5, and G-CSF), as well as pulmonary gene expression (Cxcl1/2, Ccl2/3/4, and Ifng). In vitro infection of B6 mouse-derived primary macrophages also revealed bacterial strain-dependent immune gene expression profiles. This study provided the lines of evidence that highlighted differential tissue cellular responses against Karp vs. Gilliam infection, offering a framework for future investigation of Ot strain-related mechanisms of disease pathogenesis vs. infection control.

Soluble B7-H3 in Colorectal Cancer.

We present the results of comparative ELISA of the concentration of soluble form of immunity checkpoint B7-H3 (sB7-H3) in the serum of patients with colorectal cancer (CRC) at different stages before treatment and healthy control donors. The analysis revealed a statistically significant difference between the median levels of sB7-H3 in the blood serum of CRC patients (19.66 ng/ml) and healthy donors (16.76 ng/ml) (p=0.0025). ROC analysis showed 62.9% sensitivity and 56.7% specificity for CRC patients (cut-off 17.62 ng/ml; p=0.0028). An association of sB7-H3 levels with tumor progression was revealed. We demonstrated that sB7-H3 levels were significantly lower in patients with regional metastases than in patients without metastases (p=0.039) and that sB7-H3 concentration tends to decrease at the late stages of the disease. Thus, high serum level of sB7-H3 in CRC patients can be a favorable prognostic factor in future.

Real-World Outcomes in Patients with Transformed Follicular Lymphoma Treated with CD19-Targeting CAR-T Therapy

INTRODUCTION. CD19-targeting CAR-T cell therapy has changed the treatment landscape of refractory/relapsed large B cell lymphoma, including transformed from FL (tFL). Axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel) are now FDA-approved for the treatment of tFL, but limited data are available on their clinical activity in patients (pts) with tFL since outcomes in those pts were not separately reported in registrational studies. Here, we report a single center's experience with CD19-directed CAR-T cell therapy in pts with tFL. METHODS. We performed a retrospective analysis of 54 pts with tFL treated with CAR-T cell therapy from January 2018 to December 2022. Pathological evidence of histologic transformation (HT) was confirmed. The main clinical-biological characteristics of the pts were extracted from the electronic medical records. Cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT guidelines. Progression-free (PFS) and overall survival (OS) were measured from the time of CAR-T cell infusion; PFS events were death, relapse, and disease progression. RESULTS. Within our cohort of patients with tFL, the median age was 67 years (range 42-81), 65% were male and 77% had stage III-IV disease. Eight of the pts (15%) had an ECOG Performance Status (ECOG-PS) ≥2. Median time to transformation was 27 months from original FL diagnosis (range 0 to 223), including 6 cases with composite lymphoma (FL + aggressive histology) and 4 with synchronous transformation. Twenty percent presented with high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements. Using Hans' algorithm, 85% (44/52) were identified as a germinal center B-cell origin (GCB). In 22 cases, targeted sequencing using the MSK-IMPACT panel was performed at the time of HT or prior to CAR-T. TP53 mutation/deletion was present in 50% of the cases (Figure 1). Pts received a median of 3 (range 1-9) prior lines of therapy including those for FL, and 9 pts (17%) had undergone prior autologous stem cell transplantation (SCT). Thirty-four pts (63%) were refractory to the last therapy, including 29 pts (53.7%) with primary refractory disease after HT. Forty-one pts (76%) received bridging therapy. Seventy-two percent of pts received axi-cel, 19% tisa-cel, and 9% liso-cel. CRS of any grade was seen in 43 (80%) pts with grade >3 in 3 (6%). Neurologic toxicity of any grade was observed in 20 (37%) pts with grade >3 in 7 (13%). The median duration of follow-up was 26.2 months. The overall response rate was 87%, including 67% complete response (CR). The median response duration (DOR) was 11 months, with a 2-year DOR of 42% (95% CI: 28-61%). Objective responses were achieved in pts with high-risk features such as HGBCL, TP53 mutation, and chemotherapy-refractory disease. Twenty-nine pts experienced relapse/progression during follow-up, with a median PFS for the entire cohort of 9.8 months and a 2-year PFS of 40% (95% CI: 28.3-56.3%) (Figure 2). Refractory disease after HT and high LDH serum levels were associated with a significantly lower PFS (median PFS not reached vs. 6.4 months, P=0.031; 24.4 vs. 3.2 months, P=0.003 respectively). Notably, all pts who achieved PR eventually progressed. In 23 pts with relapse, a biopsy was obtained, showing DLBCL or HGBCL morphology in all instances. Interestingly, all relapses occurred during the first 24 months. Twenty-six pts received salvage therapy after CAR-T progression, with a median of 1 line (range 1-7). Out of these, eight (31%) pts achieved a CR and went to allogenic SCT as a consolidative strategy. Twenty-two pts died during follow-up, 19 due to progression and 3 of non-lymphoma causes, including 2 of COVID-19 infection. The median OS was 31 months, and the 2-year OS rate was 57% (95% CI: 44.3-73.8%) (Figure 2). Median OS was not reached among the 36 pts who achieved a complete response. CONCLUSIONS. CD19-targeting CAR-T cell therapy is effective for pts with relapsed/refractory tFL, including patients with characteristics of poor prognosis, with efficacy and toxicity profiles comparable to that observed in previous DLBCL studies. Unfortunately, pts who relapse post-CAR-T therapy have limited effective therapeutic options available, and this currently remains an unmet medical need within the field.

Dynamic Recruitment of Inhibitory Complexes Controls Oncogenic Signaling in B-Cell Malignancies

Background and Significance: Initiation of B-cell receptor (BCR) signaling, and subsequent antigen-encounter in germinal centers represent milestones of B-lymphocyte development that are both marked by sharp increases of CD25 surface-expression. Oncogenic signaling in B-cell leukemia (B-ALL) and lymphoma also induced CD25-surface expression. While CD25 is known as an IL2-receptor chain on T- and NK-cells, the significance of its expression on B-cells was unclear. High expression levels on the surface of B-ALL cells are associated with poor clinical outcomes in pediatric (COG P9906) and adult (ECOG E2993) B-ALL cohorts. In DLBCL, aggressive disease is associated with CD25-inactivation by shedding and high serum levels of soluble CD25. Results: Our experiments based on genetic mouse models and engineered patient-derived xenografts revealed that, rather than functioning as an IL2-receptor chain, CD25 expressed on B-cells assembled an inhibitory complex including PKCδ, immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors and inhibitory phosphatases for feedback control of BCR-signaling or its oncogenic mimics. Recapitulating phenotypes of genetic ablation of PKCδ and phosphatases, conditional CD25-deletion decimated early B-cell subsets but expanded mature B-cell populations and induced autoimmunity. In B-cell malignancies arising from early stages of B-cell development (e.g. B-ALL) CD25-loss induced hyperactivation of oncogenic signaling followed by cell death. In contrast, genetic deletion of CD25 in models for mature B-cell lymphoma accelerated proliferation of malignant cells. Biochemical and interactome studies revealed a critical role of CD25 in feedback regulation of oncogenic signaling in B-cell malignancies: Signaling from BCR-ABL1 and RAS-oncogenes in B-ALL as well as oncogenic BCR-signaling in DLBCL induced PKCδ-mediated phosphorylation of CD25 on its cytoplasmic tail (S 268). Importantly, CD25-phosphorylation stabilized its expression at the cell membrane and opposed both inactivation by CD25-shedding and internalization. Moreover CD25-S 268 tail-phosphorylation enabled CD25 to recruit inhibitory receptors, including CD22, that bear ITIM-motifs for the activation of inhibitory phosphatases (e.g. SHP1, Figure 1). Thereby, the positively charged cytoplasmic tail of CD25 engages negatively charged residues in the cytoplasmic tails of the BCR signaling chain CD79B and the inhibitory CD22-ITIM. Molecular dynamics simulations revealed that the ternary complex between CD25, CD79B and CD22 enables recruitment and activation of the phosphatase SHP1 within reach of its substrate, the BCR signaling chain CD79B. Thereby, the SH2-domain of SHP1 engages the CD22-ITIM motif, while its phosphatase domain makes contact with the CD79B-ITAM to dephosphorylate and terminate BCR-signaling. This complex, while engaging and activating SHP1, is held together by CD25 ( Figure 1). To test functional consequences of destabilization of this complex, we generated a knockin mouse model carrying a single point mutation (S268A) in the cytoplasmic tail of CD25. The CD25 S268A knockin mutation abolished recruitment and activation of SHP1. In addition, the S268A-mutant failed to assemble CD22 and CD79B in complex with SHP1 to limit duration and strength of BCR-signaling. Loss of phosphatase-function and failure to terminate oncogenic signaling resulted in constitutive activation of ERK and NF-κB, autonomous Ca 2+-oscillations. Hyperactivation of oncogenic signaling resulted in exhaustion and cell death in B-ALL cells, as opposed to excessive proliferation and acceleration of disease in mature B-cell lymphoma. Conclusions: While CD25 has an established function in IL2 signal transduction in T- and NK-cells, these findings highlight the previously unrecognized role of CD25 in assembling inhibitory phosphatases to control oncogenic signaling in B-cell malignancies and provides an explanation for the common feature of CD25 shedding and high serum levels of functionally inactive soluble CD25 in aggressive B-cell lymphomas.

Interleukin-31 in serum and cerebrospinal fluid of dogs with syringomyelia

BackgroundSyringomyelia is a spinal cord cavity containing cerebrospinal fluid (CSF)-like fluid. If syringomyelia asymmetrically involves the dorsal horn grey matter of the spinal cord, affected dogs show increased signs of dysesthesia and neuropathic pain, like increased itching behaviour. In the dorsal horn, amongst others, receptors for Interleukin-31 (IL-31) can be found. IL-31 is one of the main cytokines involved in the pathogenesis of pruritus in atopic dermatitis in different species. This study investigates suspected elevated levels of IL-31 in serum and CSF of dogs showing signs of pain or increased itching behaviour related to syringomyelia. The IL-31 were measured in archived samples (52 serum and 35 CSF samples) of dogs with syringomyelia (n = 48), atopic dermatitis (n = 3) and of healthy control dogs (n = 11) using a competitive canine IL-31 ELISA.ResultsMean serum IL-31 level in dogs with syringomyelia was 150.1 pg/ml (n = 39), in dogs with atopic dermatitis 228.3 pg/ml (n = 3) and in healthy dogs 80.7 pg/ml (n = 10). Mean CSF IL-31 value was 146.3 pg/ml (n = 27) in dogs with syringomyelia and 186.2 pg/ml (n = 8) in healthy dogs. Individual patients with syringomyelia (especially dogs with otitis media or otitis media and interna or intervertebral disc herniation) showed high IL-31 levels in serum and CSF samples, but the difference was not statistically significant. IL-31 serum and CSF levels did not differ significantly in dogs with syringomyelia with or without itching behaviour and with or without signs of pain.ConclusionBased on this study, increased IL-31 levels seem not to be correlated with itching behaviour or signs of pain in dogs with syringomyelia, but might be caused by other underlying diseases.

Infliximab for medical induction of remission in Crohn's disease.

Infliximab for medical induction of remission in Crohn's disease.

An Eosinophilic Variant of Orbital Granulomatosis with Polyangiitis with Ocular Motility Disorder

Purpose: To present the case of a patient with localized orbital granulomatosis with polyangiitis (GPA) characterized by a significant ocular motility disorder, increased eosinophilia, and hyper-immunoglobulin E (hyper-IgE).Case Summary: A 61-year-old male, with no previous history of allergy, atopy, asthma, sinonasal disease, respiratory disease, or renal disease, came to our hospital due to a 2-day history of binocular diplopia. His left eye exhibited inward and upward deviation, along with gaze limitation. His vision was 20/20 in both eyes, and the pupillary light reflex and color test were normal. He had severe eyelid swelling and conjunctival injection without tenderness in his left eye, and retinal vessel congestion around the optic nerve, without proptosis. Laboratory tests revealed a positive cytoplasmic antineutrophil cytoplasmic antibody (cANCA), a normal WBC count, elevated eosinophils at 28.3% (2,462/mm<sup>3</sup>), and high serum levels of IgE (400 KU/L). Magnetic resonance imaging showed an inferolateral orbital mass with an enlarged lacrimal gland and myositis of the extraocular muscles. A biopsy of the lacrimal gland revealed nonspecific chronic inflammation with an eosinophilic infiltrate. The presence of cANCA, in combination with clinical and pathological findings, led to the diagnosis of an eosinophilic variant of localized orbital GPA. This variant was primarily confined to the orbital tissue, marked by elevated eosinophil and IgE levels, and was treated with oral steroids without requiring surgery for the ocular motility disorder.Conclusions: GPA may present as acute strabismus with orbital inflammation, even in the absence of systemic signs. Therefore, it should be considered in the differential diagnosis of unexplained acute orbital syndromes.

Meta-analysis of risk factors for cardiovascular disease in patients with rheumatoid arthritis.

Cardiovascular disease (CVD) is a common complication of rheumatoid arthritis (RA). We aimed to explore the risk factors for cardiovascular disease in patients with rheumatoid arthritis and provide a scientific basis on effective prevention and treatments for CVD in RA patients. We searched for a combination of the subject words and free words involved arthritis, rheumatoid, CVD, heart disease, vascular disease, risk factors, etc. from China Knowledge Network, Wanfang, Vip, China Biomedical Literature Database, Pubmed, Embase, Web of Science, Cochrane and other databases for documents published in public in 2000-October 2022.RevMan 5.3 and Stata14.0 analysis software was used to perform a meta-analysis of case-control and cohort studies on risk factors of CVDs in patients with RA published from 2000 to 2022.The Egger method was used to determine whether there was publication bias. Seventeen pieces of literature were included in this meta-analysis. We explored the associations between CVD and different clinical characters such as DAS28 score, rheumatoid factor, triglyceride, age, sex, C-reactive protein, total cholesterol (TC), hypertension, and D dimer. High serum levels of C-reactive protein, TC, and D-dimer, as well as hypertension, are the main risk factors for CVD in patients with RA. The OR and 95% CI of C-reactive protein were 2.06 (1.91-2.23), RR and 95% CI of TC were 1.7 (1.49-1.93), RR and 95% CI of hypertension were 3.58 (2.37-5.40), as well as OR and 95% CI of D dimer were 2.83 (1.48-5.40).Our results performed by the meta-analysis were reliable, with low publication bias existed. C-reactive protein, TC, hypertension, and D dimer are the main risk factors for CVD in patients with RA. No protective factors were found.

Association of lipoprotein(a) with severity of coronary artery atherosclerosis in patients with acute coronary syndromes

Abstract Background Elevated level of lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. However, the association of Lp(a) with acute coronary syndromes (ACS) has not been sufficiently studied. Purpose To evaluate the relationship between high serum levels of Lp(a) and (i) factors that play a role in the long-term development of the severity of coronary artery disease (CAD), (ii) extent of CAD amongst patients with ACS. Methods In this study we enrolled 74 consecutive patients hospitalized for ACS in tertiary cardiology center form December 2022 to January 2023. Patients characteristics were compared for patients with Lp(a) <75 nmol/L (53 patients) and ≥75 nmol/L (21 patients). Logistic regression analyses were performed to evaluate the relationship of Lp(a) with severity of CAD. Results In the studied population, the mean age of patients with high Lp(a) levels was 65 years. They were more likely to have arterial hypertension and hypercholesterolemia than those with normal Lp(a) levels (p <0.05). There were no significant differences in distribution of ACS subtype between groups. On univariate analysis, triple vessel CAD [odds ratio (OR) 4.22, 95% confidence interval (CI) 1.34-13.27, p = 0.014), and multivessel CAD (OR 3.05, 95% CI 1.06-8.81, p = 0.040) were significantly associated with abnormal Lp(a) levels. Multivariable determinants of of high Lp(a) levels were also triple vessel CAD (OR 4.19, 95% CI 1.33-13.26, p = 0.013), and multivessel CAD (OR 3.04, 95% CI 1.05-8.80, p = 0.042). Conclusions Lp(a) ≥75 nmol/L was closely associated with the extent and severity of CAD in patients with ACS.

Worsening renal function in patients admitted with congestive heart failure: prevalence, risk profile, and hospital readmissions

Abstract Introduction Renal function is often negatively impacted in patients with Congestive Heart Failure (CHF) due to the interplay between the heart and kidneys. Worsening Renal Function (WRF) has been associated with decreased survival, accelerated CHF progression, and higher hospitalization rate. Previous literature has thoroughly documented the effects of CHF on hospital readmissions; however, few studies have examined the impact of WRF on CHF during hospitalization, particularly not in a vulnerable population. Thus, the aim of this study was to determine the prevalence, clinical predictors, and short-term hospital readmissions of WRF among hospitalized CHF patients. Methods This was a retrospective chart review utilizing the data of 297 patients hospitalized for CHF from 2019 to 2020, either due to an exacerbation of symptoms or new-onset of disease. The analysis of our study centered around identifying the risk factors and 30-day hospital readmission rates of patients with WRF, defined as an increase in serum creatinine of ≥ 0.3 mg/dL from admission, in comparison to patients who did not develop WRF. The significance between the two groups was measured using Fisher's Exact test, Wilcoxon rank-sum, and chi-square analysis. A risk score calculated from the sum of point values assigned to each independent risk factor was created. Results Data shows that 27% of hospitalized CHF patients developed WRF. Patients with WRF had a significantly longer hospital stay and a significantly higher increase in daily Creatinine values. We identified old age, overweight, type 2 diabetes (T2D), chronic kidney disease not on dialysis, and high Furosemide dose (oral and intravenous) as independent risk factors. Other independent risk factors include abnormally high serum levels of ProBNP (≥ 9,000 ng/dL), troponin T ≥ (0.04 ng/mm), and Creatinine (≥ 1.5 mg/dL). Based on this data, a point score reflected that patients with a 6+ risk score were four times more likely to develop WRF than patients with a risk score of 0. There was no association between WRF and higher 30-day readmissions. Conclusions WRF is common in hospitalized CHF patients. Although WRF was not associated with an increased 30-day hospital readmission rate, it was associated with longer hospital length of stay and thus increased economic burden. These results highlight the benefits of implementing in-care changes to address the particular risk factors associated with WRF to prevent further progression of renal impairment in hospitalized HF patients. Future directions will incorporate other outcome variables that discern the long-term implications of WRF, including 5-year readmission rates, ESKD, and mortality.

Abstract 14930: A Case of Flecainide Toxicity Causing Wide Complex Tachycardia, Unresponsiveness, Hemodynamic Instability and Pacemaker Under-Sensing

Introduction: Flecainide toxicity (FT) is an uncommon yet potentially lethal complication. We report a case of FT precipitated by acute kidney injury (AKI) in a patient with paroxysmal atrial fibrillation (AF) and a permanent pacemaker (PPM), who presented with wide complex tachycardia (WCT) and PPM under-sensing. Case presentation: An above 85-year-old female with paroxysmal AF and a PPM presented with an episode of unresponsiveness. While en route to the ED via ambulance, she had another episode associated with hemodynamic instability precipitated by a WCT. She regained consciousness after 1 biphasic DC shock. An EKG in the ED revealed sinus rhythm with atrial under-sensing and pacing spikes during ventricular refractory period (see picture). Laboratory data were consistent with AKI and normal electrolytes levels. PPM interrogation showed atrial under-sensing. Flecainide was discontinued and following drug washout the EKG changes resolved and the QRS normalized. She was discharged on amiodarone with no recurrence of arrhythmias on follow up. Discussion: Flecainide is Class 1C Antiarrhythmic drug that blocks fast the sodium channels. Prolongation of PR interval and QRS duration, in addition to supraventricular and ventricular arrhythmias, may occur with FT. Left ventricular dysfunction, myocardial scar, and high serum levels are considered risk factors for proarrhythmia. The drug half-life is prolonged in patients with renal disease/AKI. There are limited data on PPM malfunction due to FT, but it may cause increased pacing thresholds and failure to capture. Sodium bicarbonate, lidocaine, and ECMO have been used in treatment. Conclusion: FT can lead to lethal arrhythmias and PPM malfunction. Since flecainide serum levels are not always readily available, its diagnosis can be challenging. Therefore, physicians should be aware of the clinical presentation and EKG changes that accompany FT.

Serum Soluble Interleukin-2 Receptor Levels in Hairy Cell Leukemia As a Marker of Tumor Burden with Prognostic Value and As a Tool for Disease Monitoring

Background Neoplastic cells in hairy cell leukemia (HCL) express the α chain of the interleukin-2 receptor on their surface, which is secreted in large amounts in the serum in a soluble form (sIL-2R). High serum levels of sIL-2R have previously been reported in HCL. Thus, we assessed whether serum sIL-2R levels correlated with tumor burden, represented a prognostic factor, and if they could be used as a tool for disease monitoring. Methods Serum levels of sIL-2R were measured in 59 patients affected by classical HCL followed at the Hematology Unit of Padova University Hospital. To assess whether sIL-2R levels were representative of tumor burden, we evaluated the relationship of pre-therapy sIL-2R levels with other hematologic features such as leukocyte count, the presence of splenomegaly, β-2 microglobulin levels, lactate dehydrogenase (LDH) levels, CD38 expression, the percentages of circulating hairy cells and bone marrow infiltration. In 50 patients we investigated whether post-therapy sIL-2R levels correlated with clinical response and measurable residual disease (MRD) status evaluated by immunohistochemistry according to consensus guidelines. To determine the usefulness of serum sIL-2R levels for disease monitoring, yearly serial sIL-2R levels were measured in 59 patients, including 5 (8.4%) cases in watch & wait phase and 54 (91.6%) with disease remission after therapy with purine analogues. sIL-2R kinetics were correlated with time to cytopenia (TTC) (hemoglobin <100g/L, neutrophils < 1000/µL or platelets <100.000/µL) and time to next treatment (TTNT). Serum sIL-2R levels were measured by enzyme-linked immunosorbent assay. The correlation of sIL-2R levels with other variables was evaluated by linear or logistic regression as appropriate. Medians were compared using the Mann-Whitney U test. Survival and univariate analyses for TTC and TTFT were conducted according to the Kaplan-Meier method and Cox proportional hazards model. Results The mean age of patients was 60.6 years; 10 were females (17%), and 49 were males (83%). Among treated patients, 47/54 (87%) received cladribine and 7/54 (13%) pentostatin. Pre-therapy sIL-2R levels significantly correlated with leukocyte count (r 2 = 0.13; p = 0.009), β-2 microglobulin levels (r 2 = 0.44; p < 0.001), CD38 expression (p = 0.018), the percentage of circulating hairy cells (r 2 = 0.17; p = 0.017) and the percentage of bone marrow infiltration (r 2 = 0.15; p = 0.009), but not splenomegaly (p = 0.167) or LDH levels (r 2 = 0.02; p = 0.369). We found a significant difference between serum sIL-2R levels measured before and after therapy (median 16.185 vs 599 kU/L respectively; p < 0.001), with a median reduction in sIL-2R levels of 15.628 kU/L after treatment with purine analogues. A similar decrease in sIL-2R levels after therapy was observed in 4 relapsed patients treated with rituximab-vemurafenib (median pre-therapy sIL-2R 11.460 vs. 467 kU/L after treatment, p = 0.03; median reduction 10.848 kU/L). Among responding patients, the absolute value of log10(sIL-2R) levels measured 6 months after therapy was a predictor of shorter TTNT in univariate analysis (HR 15.14; 95% CI 1.3 - 176; p = 0.03). Furthermore, sIL-2R correlated with the depth of response. Post-therapy median sIL-2R levels were significantly lower in patients achieving a complete remission (CR) versus those who did not (median 568 kU/L for CR vs. 3.272 kU/L for partial remission/stable disease; p = 0.002). A statistically significant difference was also observed in post-therapy sIL-2R levels between MRD- and MRD+ patients (median 502 vs 724 kU/L; p = 0.003) (Figure 1A). In the patients that underwent yearly serial sIL-2R measurements during follow-up, a rise from the nadir after therapy in serum sIL-2R levels of ≥ 25% between two samples was associated with both shorter TTC (HR 26.2; 95 % CI 3.44 - 200; p < 0.001) (Figure 1B) and TTNT (HR 8.83; 95 % CI 1.9 - 40.9; p < 0.001). Conclusion The consistent reduction in sIL-2R levels after therapy and their correlation with other standard disease parameters show how serum sIL-2R levels could be an effective marker of tumor burden in HCL. While more data is required to validate its use in clinical routine, sIL-2R could be used as an effective marker for disease monitoring. Moreover, given the prognostic significance of post-therapy levels, sIL-2R may represent a prognostic factor alongside MRD to identify those patients that are more likely to develop early relapse.

Hemoglobin as a prognostic marker for neurological outcomes in post-cardiac arrest patients: a meta-analysis

The aim of this study was to investigate the relationship between serum level of hemoglobin and neurological outcomes following cardiac arrest. Relevant studies were identified by searching electronic databases including PubMed, Web of Science, Cochrane Library, and Embase from June 2012 through April 2023. Articles were rigorously reviewed for their study inclusion and exclusion criteria. Pooled effect date was determined using the standardized mean difference (SMD) and 95% confidence intervals (CI). The Newcastle–Ottawa Scale was used to evaluate study quality. Subgroup analyses were conducted to determine confounding factors affecting patient outcomes. Study heterogeneity, sensitivity, and publication bias were also determined.This meta-analysis included 11 studies involving 2519 patients. Our results suggest that high serum level of hemoglobin may improve neurological prognosis(SMD = 0.60, 95%CI = 0.49–0.71, I2 = 10.85). The findings of this study indicate that serum level of hemoglobin may be associated with better neurological prognosis, perhaps an appropriate increase in serum haemoglobin levels can improve the neurological prognosis of patients in cardiac arrest.

High serum levels of inflammatory markers are associated with early recurrence in patients with high-grade serous ovarian cancer after platinum therapy

ObjectiveTo determine if inflammatory biomarkers can predict the long-term outcome of platinum therapy in patients with high-grade serous ovarian cancer. MethodsWomen diagnosed with high-grade serous epithelial ovarian cancer (n = 70) at a single institution were enrolled in a prospective serum collection study between 2005 and 2020. Seventeen markers of inflammation and oxidative stress were measured in serum samples on a chemistry analyzer. Association was tested for serum levels with progression-free survival (PFS), time to recurrence (TTR), overall survival (OS), and time to death (TTD) using Cox proportional hazards and Kaplan-Meier curves. Patient survival was censored at 10 years. ResultsHigher serum levels of LDH were associated with worse PFS (HR 2.57, p = 0.028). High serum levels of BAP (HR 0.38, p = 0.025), GSP (HR 0.40, p = 0.040), HDL-c (HR 0.27, p = 0.002), and MG (HR 0.36, p = 0.017) were associated with improved PFS. Higher expression of LDH was associated with worse OS (HR 2.16, p = 0.023). Higher levels of CK.nac (HR 0.39, p = 0.033) and HDL-c (HR 0.35, p = 0.029) were associated with improved OS. Similar outcomes were found with TTR and TTD analyses. ConclusionGeneral inflammatory biomarkers may serve as a guide for prognosis and treatment benefit. Future studies needed to further define their role in predicting prognosis or how these markers may affect response to therapy.

The use of high-sensitivity cardiac troponin I in assessing cardiac involvement and Disease prognosis in idiopathic inflammatory myopathy

ObjectivesCardiac involvement is one of the most serious complications of idiopathic inflammatory myopathy (IIM) that indicates poor prognosis. However, there is a lack of effective biomarkers for the identification of cardiac involvement and the prediction of prognosis in IIM. Here, we aimed to explore the value of different cardiac biomarkers in IIM patients.MethodsA total of 142 IIM patients in the Department of Rheumatology and Immunology, Ruijin Hospital from July 2019 to October 2022 were included in this study. The clinical characteristics, laboratory tests, treatments and prognosis were recorded. The disease activity was assessed according to the core set measures. The correlations of the serum cardiac biomarkers levels with disease activity were analyzed by the Spearman correlation test. Risk factors for cardiac involvement were evaluated by multivariate logistic regression analysis.ResultsHigher high-sensitivity cardiac troponin I (hs-cTnI) levels were associated with cardiac involvement (n = 41) in IIM patients [adjusted OR 7.810 (95% CI: 1.962–31.097); p = 0.004], independent of other serum cardiac biomarkers. The abnormal hs-cTnI had the highest AUC for distinguishing of cardiac involvement in IIM patients (AUC = 0.848, 95% CI: 0.772,0.924; p < 0.001). Besides, we found that high serum levels of hs-cTnI were significantly correlated with disease activity. Moreover, patients with higher serum levels of hs-cTnI tended to suffer from poor prognosis.ConclusionsSerum hs-cTnI testing may play a role in screening for cardiac involvement in IIM patients. Abnormal levels of serum hs-cTnI were associated with increased disease activity and poor prognosis.

Negligible role for pneumococcal surface protein A (PspA) and pneumococcal surface protein C (PspC) in the nasopharyngeal colonization of mice with a serotype 6B pneumococcal strain

Streptococcus pneumoniae colonizes the human nasopharynx asymptomatically, but it can also cause several diseases, including otitis media, pneumonia, bacteremia, and meningitis. The colonization of the nasopharynx by the bacteria is an essential step for the pneumococcus to invade other sites and cause diseases. Pneumococcal surface protein A (PspA) and Pneumococcal surface Protein C (PspC) are important virulence factors and have been described to play roles in adhesion and immune evasion. In this study, we immunized mice subcutaneously with the recombinant α-helical region of PspA and/or PspC combined with different adjuvants to assess protection against colonization with the serotype 6B strain BHN418. Though high serum levels of specific IgG were detected, none of the formulations led to reduction in the colonization of the nasopharynx. The negative result may be due to the poor induction of IgG2c, which has been previously correlated with protection against pneumococcal colonization in mice. Furthermore, BHN418 pspA and pspC single and double knockouts were evaluated in colonization experiments and no differences in bacterial load were observed. In competition assays with the wild-type strain, borderline to no reduction was observed in the loads of the knockouts. Our results contrast with data from the literature using other pneumococcal strains, showing that the role of PspA and PspC in colonization can vary depending on the background of the knockout strain studied. BHN418 has been selected for its capacity to colonize humans in experimental challenge studies and may have redundant factors that compensate for the lack of PspA and PspC during nasopharyngeal colonization of mice.

Inflammatory markers in outpatients with schizophrenia diagnosis in regular use of clozapine: a cross-sectional study.

It is known that inflammation worsen the course of schizophrenia and induce high clozapine serum levels. However, no study evaluated this change in function of clozapine daily dose in schizophrenia. We assessed the correlation between inflammation and severity symptoms in patients with schizophrenia that take and do not take clozapine. We also assessed the correlation between clozapine daily dose and inflammatory markers to patients who take this drug. Patients were recruited from Schizophrenia Ambulatory and Psychosocial Care Center of Clinical Hospital of Porto Alegre and from an association of relatives of patients with schizophrenia. Exam results, and other important clinical exam were assessed in patients record or patients were asked to show their exam in the case of outpatients. We included 104 patients, 90 clozapine users and 14 non-clozapine users. We calculate the systemic inflammatory markers [neutrophil-lymphocyte ratio (NLR), systemic immune inflammation index (SII), and the psychopathology severity by the Brief Psychiatric Rating Scaled anchored (BPRS-a)]. These variables were compared between clozapine users and non-clozapine users. It was used mean/median test according to data distributing, with study factor (SII, MLR, and PLR), the clinical outcome: severity of symptomatology (BPRS score), and clozapine daily dose as adjustment factor. Clozapine users exhibited a significantly higher neutrophil count (mean ± SD: 5.03 ± 2.07) compared to non-clozapine users (mean ± SD: 3.48 ± 1.27; p = 0.031). After controlling for comorbidity, other parameters also showed significant differences. These findings are consistent with previous studies that have demonstrated an inflammatory response following the administration of clozapine.

Role of maternal serum c-reactive protein levels in early second trimester as a marker of preterm labour: A study protocol

Preterm labour is a birth that occurs between 22 and 37 weeks after conception. The primary cause of infant death is preterm birth (PTD), which is linked to long-term neurodevelopmental and behavioural effects for preterm survivors. A maternal vascular disease pathway and an inflammation/infection pathway are two suggested pathways that have collected sufficient evidence. The identification of women who are more likely to develop PTD and the understanding of the underlying physiological mechanisms would be made possible by reliable biomarkers for these pathways. Systemic maternal infections cause elevated levels of inflammatory cytokines, which then drive the creation of prostaglandins, which can cause cervical ripening and uterine contractions that result in preterm birth. Women with signs of preterm labour have been found to have high serum levels of proinflammatory which have been prospectively linked to preterm birth. A non-specific biomarker of inflammation, C-reactive protein (CRP) is an acute phase reactant in the innate immune response. The production of C-reactive protein, a serological marker that is readily identifiable, occurs largely in the hepatocytes in response to cytokine releases from the inflammatory site. Cytokines released, by an intrauterine infection go through the maternal bloodstream to the liver, where they activate the production of CRP. Forty-eight hours after stimulation the acute-phase response has reached its maximum and a meaningful measurement can be made from a blood sample. Although the exact cause of inflammation is unknown, modest and long-lasting elevations of CRP have been linked to a range of illnesses, including normal pregnancy. Elevated CRP levels in the peripheral circulation have been connected to the presence of intrauterine infection. It has been investigated to diagnose subclinical infections using the maternal CRP concentration. The purpose of this study is to determine the link between maternal serum CRP and subsequent preterm birth in single pregnant women.

Gestational hypertension, preeclampsia, and gestational diabetes mellitus after high exposure to perfluoroalkyl substances from drinking water in Ronneby, Sweden

BackgroundLeakage of fire-fighting foam from an airfield caused contamination of the drinking water supplied to a third of the population in Ronneby, resulting in very high serum levels of predominantly perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS). The results of studies investigating the association between exposure to perfluorinated alkyl substances (PFAS) and pregnancy complications are inconsistent, and studies at high exposures of PFOS and PFHxS are lacking. ObjectivesTo investigate the association between exposure to high levels of PFAS and gestational hypertension and preeclampsia, and gestational diabetes mellitus. MethodsWe retrieved data on 27 292 childbirths between 1995 and 2013 from the National Medical Birth Register for women that had a residential address in Blekinge county for at least one year before delivery. Residential history was used as a proxy for exposure by categorizing women into high-, intermediate-, or background exposed based on their residential address during the five-year period before childbirth. Data on confounders were retrieved from administrative registers. The outcomes were defined based on International Classification of Diseases codes. We used logistic regression to estimate odds ratios (OR) for gestational hypertension and preeclampsia, and gestational diabetes mellitus. We also investigated effect modification by fetal sex. ResultsWe found no evidence of increased risk of gestational hypertension and preeclampsia (OR 0.80; CI 0.63–1.03), nor gestational diabetes (OR 1.03; CI 0.67–1.58) after high PFAS exposure. There was no effect modification by fetal sex. DiscussionThis was the first study to investigate the association between high exposure to PFOS and PFHxS and pregnancy complications. The results from this study add important knowledge to public health management as new hotspots with high levels of PFAS are continuously discovered.

THU502 CYR61, A Member Of The CCN Protein Family, Regulates IGF1 In Metastatic Prostate Cancer

Abstract Disclosure: G.L. Ortiz Hernandez: None. M. Walker: None. L. Woods-Burnham: None. R.A. Kittles: None. C.A. Casiano: None. S.L. Neuhausen: None. The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. Interestingly, CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-1 (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. We hypothesize that the interaction of CYR61 and IGF1 contributes to aggressive tumor properties (e.g., proliferation, tumorsphere formation) in PCa. Using immunoblotting, we demonstrated that CYR61 is upregulated in the androgen receptor-negative and glucocorticoid receptor-positive (AR-/GR+) metastatic cell line, PC3, and downregulated in the docetaxel-resistant cell line PC3-DR. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silenced. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not alter the MAPK pathway. We also initiated studies to determine the co-localization of CYR61 and IGF1 using immunofluorescence microscopy (IF). Based on the initial IF observations, we will proceed to examine if their interaction is primarily intra- or extra-cellular and whether interactions differ based on AR signaling. Using both PC3 and MDA-PCa-2b, which is AR+/GR+, we will co-immunoprecipitate CYR61 with IGF1 to assess intracellular interactions and use the AVidity-based EXtracellular Interaction Screen (AVEXIS) system for extracellular interactions. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Therefore, our goal is to establish the contribution of CYR61-IGF1 protein-protein interaction to PCa cell proliferation and tumor aggressiveness. Presentation: Thursday, June 15, 2023