A nomogram combining neutrophil to lymphocyte ratio (NLR) and prognostic nutritional index (PNI) to predict distant metastasis in gastric cancer.

In this study, We aim to explore the association between the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), lymphocyte to monocyte ratio (LMR) and prognostic nutritional index (PNI) and distant metastasis of gastric cancer and develop an efficient nomogram for screening patients with distant metastasis. A total of 1281 inpatients with gastric cancer were enrolled and divided into the training and validation set.Univariate, Lasso regression and Multivariate Logistic Regression Analysis was used to identify the risk factors of distant metastasis. The independent predictive factors were then enrolled in the nomogram model. The nomogram's predictive perform and clinical practicality was evaluated by receiver operating characteristics (ROC) curves, calibration curves and decision curve analysis. Multivariate Logistic Regression Analysis identified D-dimer, CA199, CA125, NLR and PNI as independent predictive factors. The area under the curve of our nomogram based on these factors was 0.838 in the training cohort and 0.811 in the validation cohort. The calibration plots and decision curves demonstrated the nomogram's good predictive performance and clinical practicality in both training and validation cohort. Therefore,our nomogram could be an important tool for clinicians in screening gastric cancer patients with distant metastasis.

The advanced lung cancer inflammation index (ALI) predicted the postoperative survival rate of patients with non-small cell lung cancer and the construction of a nomogram model.

OBJECTIVE: To investigate the prognostic significance of the advanced lung cancer inflammation index (ALI) in patients with operable non-small-cell lung carcinoma (NSCLC). By constructing the nomogram model, it can provide a reference for clinical work. METHODS: A total of 899 patients with non-small cell lung cancer who underwent surgery in our hospital between January 2017 and June 2021 were retrospectively included. ALI was calculated by body mass index (BMI) × serum albumin/neutrophil to lymphocyte ratio (NLR). The optimal truncation value of ALI was obtained using the receiver operating characteristic (ROC) curve and divided into two groups. Survival analysis was represented by the Kaplan-Meier curve. The predictors of Overall survival (OS) were evaluated by the Cox proportional risk model using single factor and stepwise regression multifactor analysis. Based on the results of multi-factor Cox proportional risk regression analysis, a nomogram model was established using the R survival package. The bootstrap method (repeated sampling 1 000 times) was used for internal verification of the nomogram model. The concordance index (C-index) was used to represent the prediction performance of the nomogram model, and the calibration graph method was used to visually represent its prediction conformity. The application value of the model was evaluated by decision curve analysis (DCA). RESULTS: The optimal cut-off value of ALI was 70.06, and the low ALI group (ALI < 70.06) showed a poor survival prognosis. In multivariate analyses, tumor location, pathological stage, neuroaggression, and ALI were independently associated with operable NSCLC-specific survival. The C index of OS predicted by the nomogram model was 0.928 (95% CI: 0.904-0.952). The bootstrap self-sampling method (B = 1000) was used for internal validation of the prediction model, and the calibration curve showed good agreement between the prediction and observation results of 1-year, 2-year, and 3-year OS. The ROC curves for 1-year, 2-year, and 3-year survival were plotted according to independent factors, and the AUC was 0.952 (95% CI: 0.925-0.979), 0.951 (95% CI: 0.916-0.985), and 0.939 (95% CI: 0.913-0.965), respectively. DCA shows that this model has good clinical application value. CONCLUSION: ALI can be used as a reliable indicator to evaluate the prognosis of patients with operable NSCLC, and through the construction of a nomogram model, it can facilitate better individualized treatment and prognosis assessment.

Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio as an Early Prognostic Marker in Patients with Ovarian Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: Presently, ovarian cancer remains the leading cause of death in gynecological malignancies. The survival rate of these patients is low, which might be caused by early metastases and delayed diagnosis. Therefore, it is crucial to investigate novel practical markers that provide early prognostic value which helps construct individualized treatment. METHODS: A thorough investigation of the neutrophil-lymphocyte ratio (NLR) and lymphocyte ratio (PLR) in ovarian cancer patients was conducted using article selection from PubMed, Cochrane, Science Direct, and Google Scholar databases. The outcomes and hazard ratio (HR) were obtained using Review Manager 5.4, and the 95% Confidence Interval (CI) result was calculated. The chief endpoints of interest in this study include overall survival (OS) and progression-free survival (PFS). RESULTS: Sixteen studies with 3,862 patients were included with a mean age of 50.6 years and a mean follow-up of 45.84 months. Multivariate studies demonstrated that a higher NLR is associated with worse PFS and OS, HR 1.35;95% CI [1.05-1.74] and HR 1.46; 95% CI [1.16-1.83] respectively. Similar results are observed with PLR and poorer PFS and OS, HR 1.62; 95% CI [1.09-2.43] and HR 1.66; 95% CI [1.12-2.46]. CONCLUSION: Pre-treatment PLR and NLR were found to be prognostic factors in determining PFS and OS in ovarian cancer. High values in pre-treatment PLR and NLR may indicate worse clinical outcomes.

DNA of neutrophil extracellular traps promote NF-κB-dependent autoimmunity via cGAS/TLR9 in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterised by persistent airway inflammation even after cigarette smoking cessation. Neutrophil extracellular traps (NETs) have been implicated in COPD severity and acute airway inflammation induced by short-term cigarette smoke (CS). However, whether and how NETs contribute to sustained airway inflammation in COPD remain unclear. This study aimed to elucidate the immunoregulatory mechanism of NETs in COPD, employing human neutrophils, airway epithelial cells (AECs), dendritic cells (DCs), and a long-term CS-induced COPD mouse model, alongside cyclic guanosine monophosphate-adenosine monophosphate synthase and toll-like receptor 9 knockout mice (cGAS--/-, TLR9-/-); Additionally, bronchoalveolar lavage fluid (BALF) of COPD patients was examined. Neutrophils from COPD patients released greater cigarette smoke extract (CSE)-induced NETs (CSE-NETs) due to mitochondrial respiratory chain dysfunction. These CSE-NETs, containing oxidatively-damaged DNA (NETs-DNA), promoted AECs proliferation, nuclear factor kappa B (NF-κB) activation, NF-κB-dependent cytokines and type-I interferons production, and DC maturation, which were ameliorated/reversed by silencing/inhibition of cGAS/TLR9. In the COPD mouse model, blocking NETs-DNA-sensing via cGAS-/- and TLR9-/- mice, inhibiting NETosis using mitoTEMPO, and degrading NETs-DNA with DNase-I, respectively, reduced NETs infiltrations, airway inflammation, NF-κB activation and NF-κB-dependent cytokines, but not type-I interferons due to IFN-α/ß receptor degradation. Elevated NETs components (myeloperoxidase and neutrophil elastase activity) in BALF of COPD smokers correlated with disease severity and NF-κB-dependent cytokine levels, but not type-I interferon levels. In conclusion, NETs-DNA promotes NF-κB-dependent autoimmunity via cGAS/TLR9 in long-term CS exposure-induced COPD. Therefore, targeting NETs-DNA and cGAS/TLR9 emerges as a potential strategy to alleviate persistent airway inflammation in COPD.

Performance evaluation of the digital morphology analyser Sysmex DI-60 for white blood cell differentials in abnormal samples.

Sysmex DI-60 enumerates and classifies leukocytes. Limited research has evaluated the performance of Sysmex DI-60 in abnormal samples, and most focused on leukopenic samples. We evaluate the efficacy of DI-60 in determining white blood cell (WBC) differentials in normal and abnormal samples in different WBC count. Peripheral blood smears (n = 166) were categorised into normal control and disease groups, and further divided into moderate and severe leucocytosis, mild leucocytosis, normal, mild leukopenia, and moderate and severe leukopenia groups based on WBC count. DI-60 preclassification and verification and manual counting results were assessed using Bland-Altman and Passing-Bablok regression analyses. The Kappa test compared the concordance in the abnormal cell detection between DI-60 and manual counting. DI-60 exhibited notable overall sensitivity and specificity for all cells, except basophils. The correlation between the DI-60 preclassification and manual counting was high for segmented neutrophils, band neutrophils, lymphocytes, and blasts, and improved for all cell classes after verification. The mean difference between DI-60 and manual counting for all cell classes was significantly high in moderate and severe leucocytosis (WBC > 30.0 × 109/L) and moderate and severe leukopenia (WBC < 1.5 × 109/L) groups. For blast cells, immature granulocytes, and atypical lymphocytes, the DI-60 verification results were similar to the manual counting results. Plasma cells showed poor agreement. In conclusion, DI-60 demonstrates consistent and reliable analysis of WBC differentials within the range of 1.5-30.0 × 109. Manual counting was indispensable in examining moderate and severe leucocytosis samples, moderate and severe leukopenia samples, and in enumerating of monocytes and plasma cells.

Pericardial effusion in patients with chronic kidney disease: A two-center study.

BACKGROUND AND AIMS: Pericardial effusion (PE) is a prevalent form of pericardial involvement in chronic kidney disease (CKD). This study aims to investigate the clinical and laboratory features associated with PE severity in patients with CKD. METHODS: In this cross-sectional study, we examined the medical records of patients admitted to tertiary hospitals with International Classification of Diseases 10th Revision (ICD-10) codes associated with CKD and PE. We included 112 CKD patients in stage 4 and 5 non-dialysis (ND) with PE for assessing the clinical and laboratory features of severity. RESULTS: Patients were divided into two categories based on the severity of PE. Seventy-two patients had mild and 40 had moderate and severe PE. Univariate analysis of demographic and laboratory features on the date of admission demonstrated that chest pain, dyspnea, serum albumin, and neutrophil-to-lymphocyte ratio (NLR) are associated with the severity of PE. The univariate analysis on the date of echocardiography showed significantly higher white blood cell count (WBC), neutrophil count (percentage and absolute count), and NLR, along with significantly lower lymphocyte percentage and serum albumin among patients with moderate and severe PE. In the multivariable analysis of laboratory features, on admission hypoalbuminemia (p-value = 0.014, OR = 4.03, CI: 1.32-12.25) and NLR greater than 5.5 (p-value = 0.015, OR = 4.22, CI: 1.32-13.50) were significantly associated with moderate and severe PE. In a parallel matter, at the time of echocardiography hypoalbuminemia (p-value = 0.004, OR = 5.38, CI: 1.74-16.65) and neutrophilia (p-value = 0.005, OR = 7.94, CI: 1.89-33.44) were significantly associated with moderate and severe PE. CONCLUSION: Despite advancements in the diagnosis and treatment of CKD, PE is still a concerning issue in these patients. This study revealed that hypoalbuminemia, neutrophilia, and NLR greater than 5.5 could be predictive factors of moderate and severe PE in CKD patients with PE. Further prospective study with larger sample size is needed to confirm these results.

The predictive value of serum inflammatory markers for the severity of cervical lesions.

OBJECTIVE: Exploring the predictive value of NLR, PLR, MLR, and SII for the severity of cervical cancer screening abnormalities in patients. METHODS: A retrospective analysis was conducted on the data of 324 patients suspected of cervical lesions due to abnormal TCT and/or HPV in our hospital from January 2023 to December 2023, who underwent colposcopy. The pathological results of colposcopic biopsy confirmed that there were 140 cases of chronic cervicitis, which classified as the group without cervical lesions. The cervical lesion group included 184 cases, including 91 cases of LSIL, 71 cases of HSIL, and 22 cases of cervical cancer. Compared the differences in preoperative peripheral blood NLR, PLR, MLR, and SII among different groups of patients, and evaluated their predictive value for the severity of cervical lesions using Receiver Operating Characteristic (ROC) curves. RESULTS: The levels of NLR, PLR, and SII in the group without cervical lesions were lower than those in the group with cervical lesions (p < 0.05), and there was no statistically significant difference in MLR (p > 0.05). The comparison of NLR among LSIL, HSIL, and cervical cancer groups showed statistically significant differences (p < 0.05), while PLR, MLR, and SII showed no statistically significant differences (p > 0.05). The AUC of peripheral blood NLR, PLR, and SII for predicting cervical lesions were 0.569, 0.582, and 0.572, respectively. The optimal cutoff values were 2.3,176.48, and 603.56. The sensitivity and specificity were 38.6% and 73.6%, 28.8% and 85.7%, 37.5% and 76.4%, respectively. At the same time, the joint testing of the three had the highest efficiency, with sensitivity of 69% and specificity of 45%. CONCLUSION: Although the peripheral blood NLR, PLR, and SII of the cervical lesions patients were higher than those without cervical lesions in cervical cancer screening abnormal patients, the predictive ROC curve discrimination was low. Therefore, it is not recommended to use preoperative peripheral blood inflammatory markers as markers for cervical cancer screening abnormal patient diversion.

Preoperative and Postoperative Platelet-Lymphocyte Ratio Is a Prognostic Marker for Patients With Soft Tissue Sarcoma Treated With Curative Resection.

BACKGROUND/AIM: Systemic inflammation has been implicated in the development and progression of cancer. Inflammatory markers have been identified as prognostic indicators in numerous malignancies. This study explored the prognostic relevance of the initial and postoperative neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) on relapse-free survival (RFS) and overall survival (OS) in patients with soft-tissue sarcoma (STS) who underwent curative resection. PATIENTS AND METHODS: We included 89 patients with STS who underwent extensive and radical resection at the Kyungpook National University Chilgok Hospital between 2004 and 2018. Kaplan-Meier curves for RFS and OS were calculated using multivariate Cox proportional models. RESULTS: A total of 67 (75.3%) patients demonstrated a high initial NLR (≥4.1) and 65 (75.3%) showed a high initial PLR (≥231). In the univariate and multivariate analyses, an elevated initial PLR ratio was significantly associated with a decreased RFS (p=0.017) and OS (p=0.003). Patients with a high PLR (PLR >231) had a median RFS of 24 months, whereas those with a low PLR (PLR ≤231) had a median RFS of 96 months. The median OS was 50 and 298 months for the high PLR and low PLR groups, respectively. Furthermore, a high postoperative PLR ratio was associated with a decreased RFS (p=0.001) and OS (p=0.038). CONCLUSION: Preoperative and postoperative PLR ratio can be used as a cost-effective prognostic marker for oncologic outcomes in patients with STS who undergo surgery.

The Systemic Immune-inflammation Index Is an Independent Prognostic Factor for Gastric Cancer Patients Who Receive Curative Treatment.

BACKGROUND/AIM: Systemic immune-inflammation index (SII) was developed and evaluated for various malignancies. This study evaluated the clinical impact of the SII in patients with gastric cancer (GC) who received curative treatment. PATIENTS AND METHODS: Patients who underwent curative resection for GC at Yokohama City University between 2005 and 2020 were chosen consecutively based on their medical records. SII was calculated as follows: platelet (cell/mm3 ×103)× neutrophil (cell/mm3)/lymphocyte (cell/mm3). Three measurements were obtained preoperatively. RESULTS: In total, 258 patients were enrolled in this study. Based on the 3- and 5-year survival rates and previous studies, we set the cutoff value of the SII to 550. The 258 patients were classified into the SII-low (n=152) and SII-high (n=106) groups, respectively. The 3- and 5-year overall survival (OS) rates were 82.6% and 78.7%, respectively, in the SII-low group and 74.5% and 61.9%, respectively, in the SII-high group. There were significant differences between the two groups (p<0.001). In the multivariate analysis of factors associated with OS, the SII was identified as an independent prognostic factor (hazard ratio=1.816; 95% confidence interval=1.075-3.069, p=0.026). Similar results were observed for recurrence-free survival. In addition, the incidence of postoperative surgical complications was 30.9% in the SII-low group and 45.2% in the SII-high group (p=0.019). CONCLUSION: The SII was an independent prognostic factor for GC. Thus, the SII may be a promising biomarker for the treatment and management of GC.

Peripheral blood immune cell parameters in patients with high-grade squamous intraepithelial lesion (HSIL) and cervical cancer and their clinical value: a retrospective study.

Objective: The objective of this study was to delineate the profile of peripheral blood lymphocytic indices in patients afflicted with high-grade squamous intraepithelial lesions (HSIL) and cervical neoplasms, and to elucidate the correlation of these hematologic markers with the clinicopathological spectra in individuals diagnosed with cervical carcinoma. Methods: We adopted a retrospective case-control modality for this investigation. An aggregate of 39 HSIL patients and 42 cervical carcinoma patients, who were treated in our facility from July 2020 to September 2023, were meticulously selected. Each case of cervical malignancy was confirmed through rigorous histopathological scrutiny. Concomitantly, 31 healthy female individuals, who underwent prophylactic health evaluations during the corresponding timeframe, were enlisted as the baseline control group. We systematically gathered and analyzed clinical demographics, as well as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), from peripheral blood samples. Pearson's correlation coefficient was deployed to dissect the interrelation between peripheral NLR and PLR concentrations and the clinicopathological features in the cervical cancer group. Results: Inter-group comparative analysis unveiled statistically substantial variances in the PLR and NLR values among the tripartite clusters (F = 36.941, 14.998, P < 0.001, respectively). Although discrepancy in NLR (P = 0.061) and PLR (P = 0.759) measures between the groups of cervical carcinoma and HSIL was not statistically appreciable, these indices were markedly elevated in the cervical carcinoma faction as juxtaposed with the normative control group (t = 5.094, 5.927; P < 0.001 for both parameters). A discernible gradation in peripheral blood PLR and NLR concentrations was noted when stratified by clinical stage and the profundity of myometrial invasion in cervical cancer subjects (P < 0.001). The correlation matrix demonstrated a positive liaison between peripheral blood PLR and the clinical gradation, as well as the invasiveness of the neoplastic cells into the muscularis propria (P < 0.05); a similar trend was observed with the NLR values (P < 0.05). Conclusion: Augmented NLR and PLR levels in peripheral blood specimens are indicative of HSIL and cervical malignancy. These hematological parameters exhibit a pronounced interconnection with clinical staging and muscular wall penetration depth, serving as potential discriminative biomarkers for the diagnosis and prognosis of cervical cancer.

The ratio of intratumoral CD15+ neutrophils to CD8+ lymphocytes predicts recurrence in patients with gastric cancer after curative resection.

BACKGROUND: An elevated neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is an independent prognostic indicator of various cancers. AIMS: In this study, we aimed to investigate the prognostic relevance of the intratumoral immune cell balance in gastric cancer. METHODS AND RESULTS: The study included 82 patients who underwent curative resection for gastric cancer. The intratumoral cluster of differentiation (CD) 15- and CD8-positive cells were evaluated using immunohistochemical staining. Additionally, clinicopathological factors and prognoses were analyzed. Patients with high intratumoral CD15/CD8 ratios had significantly lower overall survival (OS) and relapse-free survival (RFS) compared to those with low CD15/CD8 ratios (p = .0026 and p < .0001, respectively). Additionally, a high CD15/CD8 ratio was associated with lymph node metastasis (p = .019). Patients with high NLR had a significantly lower RFS than those with low NLR (p = .0050). Multivariate analysis revealed that the intratumoral CD15/CD8 ratio, NLR, and venous invasion were independent prognostic indicators of RFS (CD15/CD8 ratio: p < .001, hazard ratio (HR) = 14.7, 95% confidence interval (CI) = 3.8-56.8; NLR: p = .010, HR = 5.4, 95% CI = 1.5-19.6; venous invasion: p = .005, HR = 7.4, 95% CI = 1.8-29.7). CONCLUSION: In summary, we found that the intratumoral CD15/CD8 ratio is an independent prognostic factor following gastric cancer resection and its increase is associated with lymph node metastasis and microscopic lymph vessel invasion. Immunological evaluation with additional aspects of innate immunity may be useful in predicting cancer prognosis.

Predictive efficacy of the preoperative neutrophil-lymphocyte ratio in lymph node metastasis of cN0 hormone receptor-positive breast cancer.

Breast cancer, as the most common cancer, has surpassed lung cancer worldwide. The neutrophil-to-lymphocyte ratio (NLR) has been linked to the onset of cancer and its prognosis in recent studies. However, quite a few studies have shown that there is a link between NLR and lymph node metastases in cN0 hormone receptor-positive (HR(+)) breast cancer. The purpose of this study was to evaluate the correlation between NLR and lymph node metastases in cN0 HR(+) breast cancer patients. From January 2012 to January 2022, 220 patients with cN0 HR(+) invasive breast cancers were enrolled in this study. The relationship between NLR and pathological data was statistically examined. The receiver operating characteristic (ROC) curve was used to determine the optimal cutoff of NLR, a chi-squared test was used for the univariate analysis, and logistic analysis was used for the multivariate analysis. The NLR had an optimal cutoff of 2.4 when the Jorden index was at a maximum. Patients with axillary lymph node metastases had a higher NLR (P < 0.05). A Univariate analysis showed that there were significant differences in cN0 HR(+) breast cancer with axillary lymph node metastasis among different clinical stages, histological grades, Ki-67 levels, tumor sizes, and NLR levels (P < 0.05). Clinical stage, tumor size, and NLR were found to be independent risk factors for lymph node metastases in multifactorial analysis. In cN0 HR(+) breast cancer, NLR is an independent risk factor for lymph node metastases. An NLR ≥ 2.4 indicates an increased probability of lymph node metastases. An elevated preoperative NLR has a high predictive value for axillary lymph node metastases.

Pre-Operative Measures of Systemic Inflammation Predict Survival After Surgery for Primary Lung Cancer.

BACKGROUND: Measures of systemic inflammation (MSIs) have been developed and shown to help predict prognosis in patients with lung cancer. However, studies investigating the impact of MSIs on outcomes solely in cohorts of patients undergoing curative-intent resection of NSCLC are lacking. In the era of individualized therapies, targeting inflammatory pathways could represent a novel addition to the armamentarium of lung cancer treatment. METHODS: A multicentre retrospective review of patients who underwent primary lung cancer resection between 2012 and 2018 was undertaken. MSIs assessed were neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune inflammation index (SII), advanced lung cancer inflammation index (ALI), prognostic nutritional index (PNI) and haemoglobin albumin lymphocyte platelet (HALP) score. Cox regression analysis was performed to assess the impact of MSIs on overall survival. RESULTS: A total of 5029 patients were included in the study. Overall 90-day mortality was 3.7% (n = 185). All MSIs were significantly associated with overall survival on univariable analysis. After multivariable Cox regression analyses, lower ALI (expressed as a continuous variable) (HR 1.000, 95% CI 1.000-1.000, P = .049) and ALI <366.43 (expressed as a dichotomous variable) (HR 1.362, 95% CI 1.137-1.631, P < .001) remained independently associated with reduced overall survival. CONCLUSIONS: MSIs have emerged in this study as potentially important factors associated with survival following lung resection for NSCLC with curative intent. In particular, ALI has emerged as independently associated with long-term outcomes. The role of MSIs in the clinical management of patients with primary lung cancer requires further investigation.

Atypical granulation in neutrophils of a domestic shorthair cat.

A 13-year-old male domestic short-hair cat presented for evaluation of labored breathing, hyporexia, and lethargy. Pertinent initial diagnostics yielded leukocytosis, characterized by neutrophilia and monocytosis. Numerous small, round, magenta granules were observed within all neutrophils in Wright-Giemsa-stained blood films on the day of presentation and the day thereafter. No other neutrophil morphologic abnormalities were present, making cytoplasmic toxicity highly unlikely. Hyperadrenocorticism was diagnosed based on the lack of suppression in a low-dose dexamethasone suppression test, and without other diagnostics, the cat was discharged on trilostane therapy. Neutrophil granules did not stain with Alcian blue pH 1.0, periodic acid-Schiff (PAS), PAS and Alcian blue pH 2.5, and toluidine blue. Electron microscopy identified no differences in the morphology of the secretory granules or other neutrophil features. Metabolic screening tests of the cat's urine did not identify a genetic metabolic disorder. However, serum α- and ß -hexosaminidase (HexA and HexB) activities were 4.3% and 0% of normal controls, respectively, which is supportive of GM2-gangliosidosis, that is, Sandhoff disorder. However, the historical, clinical, and electron microscopy findings did not provide evidence to confirm this genetic defect. To the author's knowledge, this is the first case of magenta-staining granules within neutrophils in a breed other than a Birman, Siamese, or Himalayan.

Development and validation of a novel criterion of histologic healing in ulcerative colitis defined by inflammatory cell enumeration in lamina propria mucosa: A multicenter retrospective cohort in China.

BACKGROUND: Histological healing is closely associated with improved long-term clinical outcomes and lowered relapses in patients with ulcerative colitis (UC). Here, we developed a novel diagnostic criterion for assessing histological healing in UC patients. METHODS: We conducted a retrospective cohort study in UC patients, whose treatment was iteratively optimized to achieve mucosal healing at Shanghai Tenth People's Hospital of Tongji University from January 2017 to May 2022. We identified an inflammatory cell enumeration index (ICEI) for assessing histological healing based on the proportions of eosinophils, CD177 + neutrophils, and CD40L + T cells in the colonic lamina propria under high power field (HPF), and the outcomes (risks of symptomatic relapses) of achieving histological remission vs . persistent histological inflammation using Kaplan-Meier curves. Intrareader reliability and inter-reader reliability were evaluated by each reader. The relationships to the changes in the Nancy index and the Geboes score were also assessed for responsiveness. The ICEI was further validated in a new cohort of UC patients from other nine university hospitals. RESULTS: We developed an ICEI for clinical diagnosis of histological healing, i.e., Y = 1.701X 1 + 0.758X 2 + 1.347X 3 - 7.745 (X 1 , X 2 , and X 3 represent the proportions of CD177 + neutrophils, eosinophils, and CD40L + T cells, respectively, in the colonic lamina propria under HPF). The receiver operating characteristics curve (ROC) analysis revealed that Y <-0.391 was the cutoff value for the diagnosis of histological healing and that an area under the curve (AUC) was 0.942 (95% confidence interval [CI]: 0.905-0.979) with a sensitivity of 92.5% and a specificity of 83.6% ( P  <0.001). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.855 (95% CI: 0.781-0.909), and ICEI had good inter-reader reliability of 0.832 (95% CI: 0.748-0.894). During an 18-month follow-up, patients with histological healing had a substantially better outcome compared with those with unachieved histological healing ( P  <0.001) using ICEI. During a 12-month follow-up from other nine hospitals, patients with histological healing also had a lower risk of relapse than patients with unachieved histological healing. CONCLUSIONS: ICEI can be used to predict histological healing and identify patients with a risk of relapse 12 months and 18 months after clinical therapy. Therefore, ICEI provides a promising, simplified approach to monitor histological healing and to predict the prognosis of UC. REGISTRATION: Chinese Clinical Trial Registry, No. ChiCTR2300077792.

Neutrophil extracellular trap-induced ferroptosis promotes abdominal aortic aneurysm formation via SLC25A11-mediated depletion of mitochondrial glutathione.

BACKGROUND: Neutrophil extracellular traps (NETs) induce oxidative stress, which may initiate ferroptosis, an iron-dependent programmed cell death, during abdominal aortic aneurysm (AAA) formation. Mitochondria regulate the progression of ferroptosis, which is characterized by the depletion of mitochondrial glutathione (mitoGSH) levels. However, the mechanisms are poorly understood. This study examined the role of mitoGSH in regulating NET-induced ferroptosis of smooth muscle cells (SMCs) during AAA formation. METHODS: Concentrations of NET markers were tested in plasma samples. Western blotting and immunofluorescent staining were performed to detect the expression and localization of NET and ferroptosis markers in tissue samples. The role of NETs and SMC ferroptosis during AAA formation was investigated using peptidyl arginine deiminase 4 gene (Padi4) knockout or treatment with a PAD4 inhibitor, ferroptosis inhibitor or activator in an angiotensin II-induced AAA mouse model. The regulatory effect of SLC25A11, a mitochondrial glutathione transporter, on mitoGSH and NET-induced ferroptosis of SMCs was investigated using in vitro and in vivo experiments. Transmission electron microscopy was used to detect mitochondrial damage. Blue native polyacrylamide gel electrophoresis was used to analyze the dimeric and monomeric forms of the protein. RESULTS: Significantly elevated levels of NETosis and ferroptosis markers in aortic tissue samples were observed during AAA formation. Specifically, NETs promoted AAA formation by inducing ferroptosis of SMCs. Subsequently, SLC25A11 was identified as a potential biomarker for evaluating the clinical prognosis of patients with AAA. Furthermore, NETs decreased the stability and dimerization of SLC25A11, leading to the depletion of mitoGSH. This depletion induced the ferroptosis of SMCs and promoted AAA formation. CONCLUSION: During AAA formation, NETs regulate the stability of the mitochondrial carrier protein SLC25A11, leading to the depletion of mitoGSH and subsequent activation of NET-induced ferroptosis of SMCs. Preventing mitoGSH depletion and ferroptosis in SMCs is a potential strategy for treating AAA.

A study on expression of GRP78 and CHOP in neutrophil endoplasmic reticulum and their relationship with neutrophil apoptosis in the development of sepsis.

We investigated the relationship between neutrophil apoptosis and endoplasmic reticulum stress (ERS) in sepsis and its mechanism. A prospective cohort study was conducted by recruiting a total of 58 patients with sepsis. Peripheral blood samples were collected on 1, 3, 5 and 7 days after admission to the ICU. The expressions of endoplasmic reticulum specific glucose regulatory protein 78 (GRP78), C/EBP homologous protein (CHOP), apoptosis signal-regulating kinase 1 (ASK1), Bcl-2-like 11 (BIM), death receptor 5 (DR5), c-Jun N-terminal kinases (JNK) and p38 were detected by Western blot and PCR. The subcellular location of CHOP and GRP78 was observed by immunofluorescence analysis. Spearman correlation was used to analyze the correlation between the expression of chop protein and the apoptosis rate of peripheral blood neutrophils. Healthy volunteers in the same period were selected as the healthy control group. The expression of GRP78 protein was significantly elevated on the first day of ICU admission and showed a decreasing trend on the third, fifth and seventh day, but was significantly higher than the corresponding healthy control group. The expression of CHOP protein reached the highest level on the third day. The expression of chop protein in each group was significantly higher than that in the corresponding healthy control group. Immunofluorescence staining clearly showed that the CHOP protein accumulated in the nucleus, with an elevation in the intensity of GRP78. The neutrophil apoptosis rate of sepsis patients on the 1st, 3rd, 5th and 7th day of ICU stay was significantly higher than that of the healthy control group, with the highest apoptosis rate on the 3rd day, and then decreased gradually. CHOP protein expression level was significantly positively correlated with neutrophil apoptosis rate in sepsis patients. Endoplasmic reticulum stress occurs in neutrophils during the development of sepsis. GRP78 protein and CHOP protein may be involved in the pathological process of neutrophil apoptosis in sepsis.

Effector function and neutrophil cell death in the severity of sepsis with diabetes mellitus.

Sepsis, a life-threatening condition resulting from immune dysregulation, is typically triggered by bacterial infections and commonly coexists with diabetes mellitus. Neutrophils are the first responders to infection and require regulated activation to control pathogen and damage-associated molecular patterns. Dysregulation of neutrophil activation leads to uncontrolled inflammatory responses, often observed in both sepsis and diabetes patients. Neutrophil dysregulation, characterized by effector dysfunction and inadequate cell death processes, can serve as a biomarker for assessing sepsis severity, particularly in diabetic patients. This review provides information on the relationship between effector function, neutrophil cell death, and the severity of sepsis in individuals with diabetes mellitus, aiming to shed light on the mechanisms underlying sepsis progression. Topics covered in the review include an overview of effector function of neutrophil cells, mechanisms of neutrophil cell death, and dysregulation of effectors and neutrophil cell death processes in sepsis severity with diabetes mellitus.

Osteochondroprogenitor cells and neutrophils expressing p21 and senescence markers modulate fracture repair.

Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of p21+ cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, p21+ neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while p21+ OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was p21+ and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells were key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings established contextual roles of p21+ versus p16+ senescent/senescent-like cells that may be leveraged for therapeutic opportunities.