The prognostic value of the combined neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-platelet ratio (NPR) in sepsis.

Sepsis is a severe disease characterized by high mortality rates. Our aim was to develop an early prognostic indicator of adverse outcomes in sepsis, utilizing easily accessible routine blood tests. A retrospective analysis of sepsis patients from the MIMIC-IV database was conducted. We performed univariate and multivariate regression analyses to identify independent risk factors associated with in-hospital mortality within 28 days. Logistic regression was utilized to combine the neutrophil-to-lymphocyte ratio (NLR) and the neutrophil-to-platelet ratio (NPR) into a composite score, denoted as NLR_NPR. We used ROC curves to compare the prognostic performance of the models and Kaplan-Meier survival curves to assess the 28 day survival rate. Subgroup analysis was performed to evaluate the applicability of NLR_NPR in different subpopulations based on specific characteristics. This study included a total of 1263 sepsis patients, of whom 179 died within 28 days of hospitalization, while 1084 survived beyond 28 days. Multivariate regression analysis identified age, respiratory rate, neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-platelet ratio (NPR), hypertension, and sequential organ failure assessment (SOFA) score as independent risk factors for 28 day mortality in septic patients (P < 0.05). Additionally, in the prediction model based on blood cell-related parameters, the combined NLR_NPR score exhibited the highest predictive value for 28 day mortality (AUC = 0.6666), followed by NLR (AUC = 0.6456) and NPR (AUC = 0.6284). Importantly, the performance of the NLR_NPR score was superior to that of the commonly used SOFA score (AUC = 0.5613). Subgroup analysis showed that NLR_NPR remained an independent risk factor for 28 day in-hospital mortality in the subgroups of age, respiratory rate, and SOFA, although not in the hypertension subgroup. The combined use of NLR and NPR from routine blood tests represents a readily available and reliable predictive marker for 28 day mortality in sepsis patients. These results imply that clinicians should prioritize patients with higher NLR_NPR scores for closer monitoring to reduce mortality rates.

Preoperative neutrophil-to-lymphocyte ratio after chemoradiotherapy for esophageal squamous cell carcinoma associates with postoperative pulmonary complications following radical esophagectomy.

OBJECTIVES: Esophagectomy after chemoradiotherapy is associated with an increased risk of surgical complications. The significance of preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio after chemoradiotherapy in predicting pulmonary complications following radical esophagectomy in esophageal squamous cell carcinoma patients receiving preoperative chemoradiotherapy remains unknown. We aimed to investigate the utility of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in predicting the pulmonary complications of esophagectomy after preoperative chemoradiotherapy. METHODS: We retrospectively reviewed 111 consecutive patients with stage III esophageal squamous cell carcinoma who received preoperative chemoradiotherapy followed by esophagectomy between January 2009 and December 2017. Laboratory data were collected before the operation and surgical outcomes and complications were recorded. We calculated neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio and correlated them with the clinical parameters, postoperative complications, overall survival, and disease-free survival. RESULTS: Postoperative complications were observed in 75 (68%) patients, including 32 (29%) with pulmonary complications. The preoperative neutrophil-to-lymphocyte ratio of ≥ 3 (P = 0.008), clinical T4 classification (P = 0.007), and advanced stage IIIC (P = 0.012) were significantly associated with pulmonary complications. Pulmonary complication rates were 15% and 38% in patients with preoperative neutrophil-to-lymphocyte ratio of < 3 and ≥ 3, respectively. Preoperative neutrophil-to-lymphocyte ratio was not associated with the oncological stratification such as pathological T classification, pathological N classification, and pathological AJCC stage. The 3-year overall survival rates were 70% and 34% in patients with preoperative neutrophil-to-lymphocyte ratio of < 3 and ≥ 3, respectively (P = 0.0026). The 3-year disease-free survival rates were 57% and 29% in patients with preoperative neutrophil-to-lymphocyte ratio of < 3 and ≥ 3, respectively (P = 0.0055). The preoperative neutrophil-to-lymphocyte ratio of ≥ 3 was independently associated with more pulmonary complications, inferior overall survival, and worse disease-free survival. CONCLUSIONS: Elevated preoperative neutrophil-to-lymphocyte ratio after chemoradiotherapy is independently associated with higher pulmonary complication rate following radical esophagectomy and poor prognosis in patients with esophageal squamous cell carcinoma receiving preoperative chemoradiotherapy. Preoperative neutrophil-to-lymphocyte ratio is routinely available in clinical practice and our findings suggest it can be used as a predictor for pulmonary complications after esophagectomy in patients with esophageal squamous cell carcinoma receiving preoperative chemoradiotherapy.

Leveraging a neutrophil-derived PCD signature to predict and stratify patients with acute myocardial infarction: from AI prediction to biological interpretation.

BACKGROUND: Programmed cell death (PCD) has recently been implicated in modulating the removal of neutrophils recruited in acute myocardial infarction (AMI). Nonetheless, the clinical significance and biological mechanism of neutrophil-related PCD remain unexplored. METHODS: We employed an integrative machine learning-based computational framework to generate a predictive neutrophil-derived PCD signature (NPCDS) within five independent microarray cohorts from the peripheral blood of AMI patients. Non-negative matrix factorization was leveraged to develop an NPCDS-based AMI subtype. To elucidate the biological mechanism underlying NPCDS, we implemented single-cell transcriptomics on Cd45+ cells isolated from the murine heart of experimental AMI. We finally conducted a Mendelian randomization (MR) study and molecular docking to investigate the therapeutic value of NPCDS on AMI. RESULTS: We reported the robust and superior performance of NPCDS in AMI prediction, which contributed to an optimal combination of random forest and stepwise regression fitted on nine neutrophil-related PCD genes (MDM2, PTK2B, MYH9, IVNS1ABP, MAPK14, GNS, MYD88, TLR2, CFLAR). Two divergent NPCDS-based subtypes of AMI were revealed, in which subtype 1 was characterized as inflammation-activated with more vibrant neutrophil activities, whereas subtype 2 demonstrated the opposite. Mechanically, we unveiled the expression dynamics of NPCDS to regulate neutrophil transformation from a pro-inflammatory phase to an anti-inflammatory phase in AMI. We uncovered a significant causal association between genetic predisposition towards MDM2 expression and the risk of AMI. We also found that lidoflazine, isotetrandrine, and cepharanthine could stably target MDM2. CONCLUSION: Altogether, NPCDS offers significant implications for prediction, stratification, and therapeutic management for AMI.

Association between lower neutrophil-to-albumin ratio and early neurological improvement in patients with acute cerebral infarction after intravenous thrombolysis.

Elevated neutrophil counts and decreased albumin levels have been linked to an unfavorable prognosis in acute cerebral infarction (ACI). The objective of this study is to explore the correlation between the neutrophil-to-albumin ratio (NAR) and the early neurological improvement (ENI) of ACI patients following intravenous thrombolysis (IVT). ACI patients who underwent IVT between June 2019 and June 2023 were enrolled. The severity of ACI was assessed using the National Institutes of Health Stroke Scale (NIHSS). ENI was defined as a reduction in NIHSS score of ≥ 4 or complete resolution of neurological deficit within 24 h after IVT. Propensity score match (PSM) and logistic regression analysis were used to explore the correlation between these variables and the early neurological outcomes of patients. A total of 545 ACI patients were included, with 253 (46.4 %) experiencing ENI. Among the 193 pairs of patients after PSM, there was a significant association between NAR and ENI (OR, 0.89; 95 % CI, 0.85-0.94; p < 0.001). The restricted cubic splines analysis revealed a significant nonlinear correlation between NAR and ENI (p for nonlinear = 0.0004; p for overall = 0.0002). The optimal cutoff for predicting ENI was determined as a NAR level of 10.20, with sensitivity and specificity values of 73.6 % and 60.9 %. NAR levels are associated with ENI in ACI patients after IVT. The decreased levels of NAR indicate an increased likelihood of post-thrombolysis ENI in ACI patients.

Identification of lignans as selective cyclooxygenase-2 inhibitors from the extract of Acanthopanacis cortex.

Acanthopanacis cortex (the dried root bark of Acanthopanax gracilistylus W. W. Smith) has been used for the treatment of rheumatic diseases in China for over 2000 years. Four previously undescribed lignans (1-4) and 12 known lignans (5-16) were isolated from Acanthopanacis cortex. In this study, the inhibitory activities of compounds 1-16 against neutrophil elastase (NE), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) are reported. The results show that compounds 1-16 exhibit weak inhibitory activities against NE and COX-1. However, compounds 2, 6-8 and 13-16 demonstrate better COX-2 inhibitory effects with IC50 values from 0.75 to 8.17 µΜ. These findings provide useful information for the search for natural selective COX-2 inhibitors.

Clinical study of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in hypertriglyceridemia-induced acute pancreatitis and acute biliary pancreatitis with persistent organ failure.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel inflammatory indicators that can be used to predict the severity and prognosis of various diseases. We categorize acute pancreatitis by etiology into acute biliary pancreatitis (ABP) and hypertriglyceridemia-induced acute pancreatitis (HTGP). AIM: To investigate the clinical significance of NLR and PLR in assessing persistent organ failure (POF) in HTGP and ABP. METHODS: A total of 1450 patients diagnosed with acute pancreatitis (AP) for the first time at Shanxi Bethune Hospital between January 2012 and January 2023 were enrolled. The patients were categorized into two groups according to the etiology of AP: ABP in 530 patients and HTGP in 241 patients. We collected and compared the clinical data of the patients, including NLR, PLR, and AP prognostic scoring systems, within 48 h of hospital admission. RESULTS: The NLR (9.1 vs 6.9, P < 0.001) and PLR (203.1 vs 160.5, P < 0.001) were significantly higher in the ABP group than in the HTGP group. In the HTGP group, both NLR and PLR were significantly increased in patients with severe AP and those with a SOFA score ≥ 3. Likewise, in the ABP group, NLR and PLR were significantly elevated in patients with severe AP, modified computed tomography severity index score ≥ 4, Japanese Severity Score ≥ 3, and modified Marshall score ≥ 2. Moreover, NLR and PLR showed predictive value for the development of POF in both the ABP and HTGP groups. CONCLUSION: NLR and PLR vary between ABP and HTGP, are strongly associated with AP prognostic scoring systems, and have predictive potential for the occurrence of POF in both ABP and HTGP.

Application of neutrophil-lymphocyte ratio and red blood cell distribution width in diabetes mellitus complicated with heart failure.

BACKGROUND: Accumulating clinical evidence has shown that diabetes mellitus (DM) is a serious risk factor for cardiovascular disorders and an important factor for adverse cardiovascular events. AIM: To explore the value of the combined determination of the neutrophil-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) in the early diagnosis and prognosis evaluation of DM complicated with heart failure (HF). METHODS: We retrospectively analyzed clinical data on 65 patients with type 2 DM (T2DM) complicated with HF (research group, Res) and 60 concurrent patients with uncomplicated T2DM (control group, Con) diagnosed at Zhejiang Provincial People's Hospital between January 2019 and December 2021. The NLR and RDW values were determined and comparatively analyzed, and their levels in T2DM + HF patients with different cardiac function grades were recorded. The receiver operating characteristic (ROC) curves were plotted to determine the NLR and RDW values (alone and in combination) for the early diagnosis of HF. The correlation between NLR and RDW with the presence or absence of cardiac events was also investigated. RESULTS: Higher NLR and RDW levels were identified in the Res vs the Con groups (P < 0.05). The NLR and RDW increased gradually and synchronously with the deterioration of cardiac function in the Res group, with marked differences in their levels among patients with grade II, III, and IV HF (P < 0.05). ROC curve analysis revealed that NLR combined with RDW detection had an area under the curve of 0.915, a sensitivity of 76.9%, and a specificity of 100% for the early diagnosis of HF. Furthermore, HF patients with cardiac events showed higher NLR and RDW values compared with HF patients without cardiac events. CONCLUSION: NLR and RDW were useful laboratory indicators for the early diagnosis of DM complicated with HF, and their joint detection was beneficial for improving diagnostic efficiency. Additionally, NLR and RDW values were directly proportional to patient outcomes.

Self-extinguishing relay waves enable homeostatic control of human neutrophil swarming.

Neutrophils collectively migrate to sites of injury and infection. How these swarms are coordinated to ensure the proper level of recruitment is unknown. Using an ex vivo model of infection, we show that human neutrophil swarming is organized by multiple pulsatile chemoattractant waves. These waves propagate through active relay in which stimulated neutrophils trigger their neighbors to release additional swarming cues. Unlike canonical active relays, we find these waves to be self-terminating, limiting the spatial range of cell recruitment. We identify an NADPH-oxidase-based negative feedback loop that is needed for this self-terminating behavior. We observe near-constant levels of neutrophil recruitment over a wide range of starting conditions, revealing surprising robustness in the swarming process. This homeostatic control is achieved by larger and more numerous swarming waves at lower cell densities. We link defective wave termination to a broken recruitment homeostat in the context of human chronic granulomatous disease.

Anti-CTLA-4 m2a Antibody Exacerbates Cardiac Injury in Experimental Autoimmune Myocarditis Mice By Promoting Ccl5-Neutrophil Infiltration.

The risk for suffering immune checkpoint inhibitors (ICIs)-associated myocarditis increases in patients with pre-existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry are used to decipher how anti-cytotoxic T lymphocyte antigen-4 m2a antibody (anti-CTLA-4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti-CTLA-4 m2a antibody increases cardiac fibroblast-derived C-X-C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1-Cxcr2 chemotaxis. It is identified that the C-C motif chemokine ligand 5 (Ccl5)-neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF-κB signaling, and cellular response to interferon-gamma and that the Ccl5-neutrophil subpopulation and its-associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti-CTLA-4 m2a antibody-induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5-neutrophil subpopulation plays a critical role in aggravating anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs-associated myocarditis.

Limited impact of traumatic brain injury on the post-traumatic inflammatory cellular response.

PURPOSE: Trauma triggers a systemic inflammatory cellular response due to tissue damage, potentially leading to a secondary immune deficiency. Trauma severity is quantified by the Injury Severity Score (ISS). Severe Traumatic Brain Injury (TBI) is associated with high ISSs due to high lethality, despite limited tissue damage. Therefore, ISS might overestimate the post-traumatic inflammatory cellular response. This study investigated the effect of TBI on the occurrence of different systemic neutrophil phenotypes as alternative read-out for systemic inflammation. METHODS: A single-center retrospective cohort study was conducted at a level-1 trauma center. Patients aged ≥ 18 years, admitted between 01-03-2021-01-11-2022 and providing a diagnostic blood sample were included. Four groups were created: isolated TBI, isolated non-TBI, multitrauma TBI and multitrauma non-TBI. Primary outcome was occurrence of different neutrophil phenotypes determined by automated flow cytometry. Secondary outcome was infectious complications. RESULTS: In total, 404 patients were included. TBI and non-TBI patients demonstrated similar occurrences of different neutrophil phenotypes. However, isolated TBI patients had higher ISSs than their isolated non-TBI controls who suffered similar post-traumatic inflammatory cellular responses. Regardless of the type of injury, patients exhibiting higher systemic inflammation had a high infection risk. CONCLUSION: When TBI is involved, ISS tends to be higher compared to similar patients in the absence of TBI. However, TBI patients did not demonstrate an increased inflammatory cellular response compared to non-TBI patients. Therefore, TBI does not add much to the inflammatory cellular response in trauma patients. The degree of the inflammatory response was related to the incidence of infectious complications.

Neutrophils actively swell to potentiate rapid migration.

While the involvement of actin polymerization in cell migration is well-established, much less is known about the role of transmembrane water flow in cell motility. Here, we investigate the role of water influx in a prototypical migrating cell, the neutrophil, which undergoes rapid, directed movement to sites of injury, and infection. Chemoattractant exposure both increases cell volume and potentiates migration, but the causal link between these processes are not known. We combine single-cell volume measurements and a genome-wide CRISPR screen to identify the regulators of chemoattractant-induced neutrophil swelling, including NHE1, AE2, PI3K-gamma, and CA2. Through NHE1 inhibition in primary human neutrophils, we show that cell swelling is both necessary and sufficient for the potentiation of migration following chemoattractant stimulation. Our data demonstrate that chemoattractant-driven cell swelling complements cytoskeletal rearrangements to enhance migration speed.

Clinical characteristics and outcome of double-seropositive patients with anti-glomerular basement membrane antibodies and anti-neutrophil cytoplasmic antibodies.

OBJECTIVE: To explore the clinical characteristics of double-seropositive patients (DPPs) with anti-glomerular basement membrane (Anti-GBM) antibodies and anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: We collected patients with both ANCA and anti-GBM positive glomerulonephritis who were hospitalized in the Department of Nephrology at the First Affiliated Hospital of Nanjing Medical University from January 2010 to August 2022. Retrospective analysis of the baseline clinical characteristics of patients and follow-up to explore relevant factors affecting renal and patient survival. RESULTS: A total of 386 patients, including 69 ANCA negative anti-GBM glomerulonephritis patients, 296 anti-GBM negative ANCA associated vasculitis (AAV) patients, and 21 DPPs were enrolled in this study. Among the 21 DPPs aged 68.0 years (59.5, 74.0), there were 11 males and 10 females. The median serum creatinine at diagnosis was 629.0 (343.85, 788.75) µmol/L, and the median eGFR (CKD-EPI) was 7.58 (4.74, 13.77) mL/min. Fifteen cases (71.4 %) underwent initial RRT. After a follow-up of 40.0 (11.0, 73.0) months, 13 out of 21 DPPs (61.9 %) received maintenance RRT, while 49 out of 69 (71.0 %) ANCA negative anti-GBM-GN patients and 124 out of 296 (41.9 %) anti-GBM negative AAV patients received maintenance RRT (P < 0.001). Kaplan-Meier survival analysis showed that DPPs and ANCA negative anti-GBM-GN patients were more likely to progress to ESRD than anti-GBM negative AAV patients (P = 0.001). Among the 21 patients with DPPs, renal survival was significantly better in patients with better initial renal function, including those who did not receive initial RRT (P = 0.003), with lower serum creatinine levels (Cr < 629.0 µmol/L, P = 0.004) and higher eGFR levels (eGFR ≥ 7.60 ml/min, P = 0.005) than those with poor initial renal function. At the end of follow-up, 14 out of 21 DPPs (66.7 %) survived. Survival analysis showed no significant difference among patients in DPPs group, ANCA negative anti-GBM-GN group, and anti-GBM negative AAV group. CONCLUSIONS: DPPs and ANCA negative anti-GBM-GN patients were more likely to progress to ESRD than anti-GBM negative AAV patients. In DPPs, the poor renal function at diagnosis might be a risk factor associated with poor renal survival.

Patients with High Baseline Neutrophil-to-Lymphocyte Ratio Exhibit Better Response to Filgotinib as Treatment for Rheumatoid Arthritis.

INTRODUCTION: High baseline neutrophil-to-lymphocyte ratio (NLR) in rheumatoid arthritis (RA) has been associated with positive responses to biologic tumor necrosis factor inhibition and negative responses to conventional synthetic disease-modifying antirheumatic drug (csDMARD) triple therapy. Datasets from three randomized clinical trials in patients with RA were used to test the hypothesis that baseline NLR is associated with improved clinical response to filgotinib in methotrexate (MTX)-naïve or MTX-experienced RA populations. METHODS: Patients from FINCH 1 (inadequate response to MTX, MTX-IR; NCT02889796), FINCH 2 (inadequate response to biologic DMARDs; NCT02873936), and FINCH 3 (MTX-naïve; NCT02886728) were classified as baseline NLR-High or baseline NLR-Low based on a previously published cut point of 2.7. In total, 3365 patients were included across the three studies. Differences in clinical outcomes and patient-reported outcomes (PROs) were determined using linear-regression models. RESULTS: Control-arm patients (placebo + MTX/placebo + csDMARD) classified as NLR-High exhibited worse continuous clinical and PRO responses at week 12 across clinical trials compared to NLR-Low patients. In contrast, NLR-High patients who received FIL 200 mg + MTX/csDMARD exhibited consistently better responses after 12 weeks compared to NLR-Low patients across clinical trials, clinical endpoints, and PROs. These trends were most prominent among the MTX-IR population. CONCLUSION: The 2.7 baseline NLR cut point could be used to enrich for patients most likely to benefit from the addition of filgotinib to background MTX/csDMARD. Use of baseline NLR as part of therapeutic decision-making would not require additional diagnostics and could contribute to improved outcomes for patients with RA. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02889796; NCT02873936; NCT02886728.

Rheumatoid arthritis is a disease that results in swollen and painful joints. There is currently no method to determine which treatment will work best for an individual patient. However, there may be identifying markers found in the blood that could indicate how a patient will respond to treatment. One of these possible markers is a ratio of two types of white blood cells, neutrophils and lymphocytes, which are part of the body's immune system and help the body detect and fight infection and other diseases. This ratio is referred to as the neutrophil-to-lymphocyte ratio. The current study evaluated whether the neutrophil-to-lymphocyte ratio at the beginning of treatment was associated with rheumatoid arthritis treatment outcomes. Blood test results were used from 3365 patients receiving filgotinib (a medicine used to treat rheumatoid arthritis) or other therapies as part of the FINCH clinical trials. Patients were classified as having a high or low neutrophil-to-lymphocyte ratio at the start of treatment. Patients receiving filgotinib over 24 weeks who had a high neutrophil-to-lymphocyte ratio showed less disease activity than patients whose ratio was low. This study provides support for the use of the neutrophil-to-lymphocyte ratio as a way to help determine whether a patient would benefit from filgotinib as part of their rheumatoid arthritis treatment and may help improve rheumatoid arthritis treatment outcomes.

Molecular Characteristics and Pretreatment Neutrophil-to-Lymphocyte Ratio as Predictors of Durable Clinical Benefit from Immune Checkpoint Inhibition in Non-Small Cell Lung Cancer.

BACKGROUND: Prior research in non-small cell lung cancer (NSCLC) has shown that tumors with specific driver mutations may be less likely to respond to immune checkpoint inhibitors (ICI). In this analysis, we evaluated the characteristics of patients with durable clinical benefit (DCB) to ICI compared to those with no durable clinical benefit (NDB), with emphasis on the role of molecular alterations in EGFR, ALK, and ROS1 and pretreatment neutrophil-to-lymphocyte ratio (NLR). METHODS: We retrospectively collected clinical characteristics and outcomes for patients who initiated ICI monotherapy for advanced NSCLC at Stanford University between April 2015 and May 2018. Patients were classified as having DCB if time on ICI therapy was greater than or equal to 180 days, or NDB if less than 180 days. Outcomes included best radiographic benefit while on ICI and survival from time of ICI initiation. RESULTS: Of 123 patients treated with ICI for NSCLC, 28 patients had DCB (23%), while 95 had NDB (77%). Median overall survival from initiation of ICI in the 33 patients with molecular alterations in EGFR (n = 31), ALK, or ROS1 and NLR of 5.9 or higher was 2.0 months, compared to 8.1 months in patients with these genomic alterations and NLR less than 5.9. Median overall survival in patients without alterations in EGFR, ALK, or ROS1 and NLR of 5.9 or higher was 4.3 months, compared to 12.1 months in patients with NLR less than 5.9 (P = .023). CONCLUSIONS: Elevation in pretreatment NLR was associated with significantly lower overall median survival from initiation of ICI, particularly when in combination with NSCLC with alterations in EGFR, ALK, or ROS1. This finding could influence clinical practice as NLR is readily available through routine blood testing.

Dynamic change of neutrophil-to-lymphocyte ratio and its predictive value of prognosis in acute ischemic stroke.

OBJECTIVE: The present research aimed to explore the dynamic change of the neutrophil-to-lymphocyte ratio (NLR) and its relationship with functional outcome following an acute ischemic stroke (AIS), whether receiving intravenous thrombolysis (IVT) or not. METHODS: We retrospectively analyzed data that were prospectively acquired from patients with AIS treated with IVT or not. For patients receiving IVT, the NLR was based on a blood test performed prior to IVT (d0) and at different time points after disease onset (d1, d3, d7). In addition, in the non-IVT group, the NLR was obtained at different time points after disease onset (d1, d3, d7). Follow-ups were performed 3 months after onset via telephone. In addition, a good outcome was defined as a modified Rankin scale (mRS) ≤1; a poor outcome means 2 ≤ mRS ≤ 6. RESULTS: A total of 204 AIS patients were included in this study. The NLR presented a dynamic change as it increased to its peak at day 1 and gradually declined to its baseline at day 7, no matter whether patients were receiving IVT or not. Patients with poor outcomes have a higher NLR at various time points. The results of multivariate logistic regression analysis demonstrated that the National Institutes of Health Stroke Scale (NIHSS), NLR d1, NLR d3, and NLR d7 were independently associated with functional outcomes. The area under the receiver operating characteristic curve of NLR in predicting outcomes was as follows: NLR d3 demonstrated robust predictive power within the IVT therapy cohort, whereas NLR d7 was predictive in the non-IVT cohort. However, the most potent predictor emerged as the combination of NIHSS and NLR. CONCLUSION: NLR has the potential to predicate diagnosis for AIS, especially when combined with the NIHSS score.

Transcriptional pathobiology and multi-omics predictors for Parkinson's disease.

Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale whole-blood total RNA-seq dataset from the Accelerating Medicine Partnership in Parkinson's Disease (AMP PD) program to identify PD-associated RNAs, including both known genes and novel circular RNAs (circRNA) and enhancer RNAs (eRNAs). There were 1,111 significant marker RNAs, including 491 genes, 599 eRNAs, and 21 circRNAs, that were first discovered in the PPMI cohort (FDR < 0.05) and confirmed in the PDBP/BioFIND cohorts (nominal p < 0.05). Functional enrichment analysis showed that the PD-associated genes are involved in neutrophil activation and degranulation, as well as the TNF-alpha signaling pathway. We further compare the PD-associated genes in blood with those in post-mortem brain dopamine neurons in our BRAINcode cohort. 44 genes show significant changes with the same direction in both PD brain neurons and PD blood, including neuroinflammation-associated genes IKBIP, CXCR2, and NFKBIB. Finally, we built a novel multi-omics machine learning model to predict PD diagnosis with high performance (AUC = 0.89), which was superior to previous studies and might aid the decision-making for PD diagnosis in clinical practice. In summary, this study delineates a wide spectrum of the known and novel RNAs linked to PD and are detectable in circulating blood cells in a harmonized, large-scale dataset. It provides a generally useful computational framework for further biomarker development and early disease prediction.

Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2.

Immune escape is the main reason that immunotherapy is ineffective in hepatocellular carcinoma (HCC). Here, this study illustrates a pathway mediated by neutrophil extracellular traps (NETs) that can promote immune escape of HCC. Mechanistically, we demonstrated that NETs up-regulated CD73 expression through activating Notch2 mediated nuclear factor kappa B (NF-κB) pathway, promoting regulatory T cells (Tregs) infiltration to mediate immune escape of HCC. In addition, we found the similar results in mouse HCC models by hydrodynamic plasmid transfection. The treatment of deoxyribonuclease I (DNase I) could inhibit the action of NETs and improve the therapeutic effect of anti-programmed cell death protein 1 (PD-1). In summary, our results revealed that targeting of NETs was a promising treatment to improve the therapeutic effect of anti-PD-1.

The role of anti-citrullinated protein antibody in pathogenesis of RA.

Rheumatoid arthritis (RA) is a common autoimmune rheumatic disease that causes chronic synovitis, bone erosion, and joint destruction. The autoantigens in RA include a wide array of posttranslational modified proteins, such as citrullinated proteins catalyzed by peptidyl arginine deiminase4a. Pathogenic anti-citrullinated protein antibodies (ACPAs) directed against a variety of citrullinated epitopes are abundant both in plasma and synovial fluid of RA patients. ACPAs play an important role in the onset and progression of RA. Intensive and extensive studies are being conducted to unveil the mechanisms of RA pathogenesis and evaluate the efficacy of some investigative drugs. In this review, we focus on the formation and pathogenic function of ACPAs.

tRF-His-GTG-1 enhances NETs formation and interferon-α production in lupus by extracellular vesicle.

BACKGROUND: Hyperactive neutrophil extracellular traps (NETs) formation plays a crucial role in active severe systemic lupus erythematosus (SLE). However, what triggers the imbalance in dysregulated NETs formation in SLE is elusive. Transfer RNA-derived small RNAs (tsRNAs) are novel non-coding RNAs, which participate in various cellular processes. We explore the role of tsRNAs on NETs formation in SLE. METHODS: We analyzed the levels of NETs DNA and platelet-derived extracellular vesicles (pEVs) from 50 SLE patients and 20 healthy control subjects. The effects of pEVs on NETs formation were evaluated by using immunofluorescence assay and myeloperoxidase-DNA PicoGreen assay. The regulatory mechanism of pEVs on NETs formation and inflammatory cytokines production were investigated using an in vitro cell-based assay. RESULTS: Increased circulating NETs DNA and pEVs were shown in SLE patients and were associated with disease activity (P < 0.005). We demonstrated that SLE patient-derived immune complexes (ICs) induced platelet activation, followed by pEVs release. ICs-triggered NETs formation was significantly enhanced in the presence of pEVs through Toll-like receptor (TLR) 8 activation. Increased levels of tRF-His-GTG-1 in pEVs and neutrophils of SLE patients were associated with disease activity. tRF-His-GTG-1 interacted with TLR8 to prime p47phox phosphorylation in neutrophils, resulting in reactive oxygen species production and NETs formation. Additionally, tRF-His-GTG-1 modulated NF-κB and IRF7 activation in neutrophils upon TLR8 engagement, resulting IL-1ß, IL-8, and interferon-α upregulation, respectively. CONCLUSIONS: The level of tRF-His-GTG-1 was positively correlated with NETs formation in SLE patients; tRF-His-GTG-1 inhibitor could efficiently suppress ICs-triggered NETs formation/hyperactivation, which may become a potential therapeutic target.

Neutrophils and platelets are key members in the immunopathogenesis of SLE. EVs play a key role in intercellular communication. Abnormal NETs formation promotes vascular complications and organ damage in SLE patients. tsRNA is a novel regulatory small non-coding RNA and participates in diverse pathological processes. Herein, we showed that SLE patient-derived ICs activates platelets directly, followed by intracellular tRF-His-GTG-1 upregulation, which is loaded into pEVs. The pEV-carried tRF-His-GTG-1 could interact with TLR8 in neutrophils, followed by activation of the downstream signaling pathway, including p47phox-NOX2-ROS, which causes NETs enhancement, while IRF7 promotes the expression of IFN-α. The tRF-His-GTG-1 inhibitor could suppress efficiently SLE ICs-induced NETs formation and pEVs primed NETs enhancement. This study offers new molecular machinery to explain the association between the platelets-derived tsRNAs, pEVs, and hyperactive NETs formation in lupus. tRF-His-GTG-1 may serve as a potential therapeutic target and help to advance our understanding of tsRNAs in SLE pathogenesis.

RNAseq of INOCA patients identifies innate, invariant, and acquired immune changes: potential autoimmune microvascular dysfunction.

Background: Ischemia with non-obstructive coronary arteries (INOCA) is a major clinical entity that involves potentially 20%-30% of patients with chest pain. INOCA is typically attributed either to coronary microvascular disease and/or vasospasm, but is likely distinct from classical coronary artery disease (CAD). Objectives: To gain insights into the etiology of INOCA and CAD, RNA sequencing of whole blood from patients undergoing both stress testing and elective invasive coronary angiography (ICA) was conducted. Methods: Stress testing and ICA of 177 patients identified 40 patients (23%) with INOCA compared to 39 controls (stress-, ICA-). ICA+ patients divided into 38 stress- and 60 stress+. RNAseq was performed by Illumina with ribosomal RNA depletion. Transcriptome changes were analyzed by DeSeq2 and curated by manual and automated methods. Results: Differentially expressed genes for INOCA were associated with elevated levels of transcripts related to mucosal-associated invariant T (MAIT) cells, plasmacytoid dendritic cells (pcDC), and memory B cells, and were associated with autoimmune diseases such as rheumatoid arthritis. Decreased transcripts were associated with neutrophils, but neutrophil transcripts, per se, were not less abundant in INOCA. CAD transcripts were more related to T cell functions. Conclusions: Elevated transcripts related to pcDC, MAIT, and memory B cells suggest an autoimmune component to INOCA. Reduced neutrophil transcripts are likely attributed to chronic activation leading to increased translation and degradation. Thus, INOCA could result from stimulation of B cell, pcDC, invariant T cell, and neutrophil activation that compromises cardiac microvascular function.