A little ER stress isn't bad: the IRE1α/XBP1 pathway shapes ILC3 functions during intestinal inflammation.

Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn's disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.

Smudge cells.

Smudge cells can be defined as ruptured or destroyed cells - most commonly lymphocytes where cytoplasm and nuclei get smudged during smear test of the patient's blood/preparation of slides. When finding smudge cells, it is recommended to control the lab work frequently. If a persistent or higher number of smudge cells are found during 3 months, it should lead to a referral to the hematologist. The purpose of this review is to give an overview of smudge cells and conditions in which they can be found, as well as management of the findings.

Predictability of the Delta Neutrophil Index and Other Blood Parameters on Perinatal Outcomes in Pregnant Women With Systemic Lupus Erythematosus.

PROBLEM: This study aimed to evaluate the predictive value of delta neutrophil index (DNI), a peripheral blood parameter, on perinatal outcomes in pregnant women with systemic lupus erythematosus (SLE). METHOD OF STUDY: One hundred eighty-one participants, 78 pregnant women with SLE, and 103 healthy pregnant women were included in this retrospective study. Peripheral blood parameters including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and DNI taken in the first trimester were compared between groups. RESULTS: NLR, PLR, and DNI were significantly higher in the SLE group (p = 0.027, p = 0.007, p = 0.0001, respectively). The same parameters were not found to be significant in determining disease activity in pregnant women with SLE (p > 0.05). When the predictive value of DNI for SGA in pregnancies with SLE was evaluated by receiver operating characteristic curve (ROC), the area under the ROC curve (AUC) was 0.666 (95% CI; 0.544-0.788, p = 0.018) with 84.6% sensitivity, 53.8% specificity, 56.0% PPV, and 78.1% NPV at a cut-off value of 0.16. The predictive value of DNI according to ROC for stillbirth in pregnancies with SLE was AUC 0.731 (95% CI: 0.539-0.923, p = 0.019) with a cut-off value of 0.17, sensitivity of 90%, specificity of 51.5%, PPV of 58.5%, and NPV of 87.2%. CONCLUSIONS: Although DNI's prediction of SGA and stillbirth in pregnant women with SLE is encouraging, it needs more evidence from prospective studies with larger series.

The coagulation status in women of endometriosis with stage IV.

BACKGROUND: Endometriosis is considered as a systemic disease with the presence of proinflammatory cytokines in the circulation, which drives hypercoagulable state of endometriosis. Currently, endometriosis is classified into four stages: I (minimal), II (mild), III (moderate) and IV (severe). The aim of this study is to investigate the correlations between inflammatory markers and coagulation factors in patients diagnosed of endometriosis with stage IV. METHODS: This retrospective case-control study included 171 endometriosis patients with stage IV and 184 controls. Continuous data were expressed by mean ± standard deviation. Mann-Whitney U and χ2 tests were used to compare the medians and frequencies among the groups. Spearman analysis was conducted to determine the correlation among the measured parameters. The diagnostic values of the parameters differentiating endometriomas were tested by receiver operating characteristic (ROC) curve. RESULTS: The time of activated partial thromboplastin time (APTT) was decreased and the concentration of fibrinogen (FIB) and neutrophil-to-lymphocyte ratio (NLR) were increased in women of endometriosis with stage IV. The APTT were negatively correlated with NLR while the concentrations of FIB were positively correlated with NLR. The ROC analysis showed that the Area under the curve (AUC) of FIB was 0.766 (95% confidence interval:0.717-0.814) with sensitivity and specificity reaching 86.5 and 60.9%, respectively. The AUC of CA125 and CA199 was 0.638 (95% confidence interval: 0.578-0.697), 0.71 (95% confidence interval: 0.656-0.763) with sensitivity and specificity reaching 40.9 and 91.8%, 80.7 and 56.5% respectively. The combination of these factors showed the highest AUC of 0.895 (0.862-0.927) with sensitivity of 88.9% and specificity of 77.7%. CONCLUSION: In the present study, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV. Moreover, the coagulation factors combined with CA125 and CA199 were more reliable for identifying the endometriosis with stage IV.

Lymphocytes as a living drug for cancer.

Using a patient's lymphocytes is approved to treat melanoma and has wider applications.

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.

Association of Neutrophil-Lymphocyte Ratio and Red Blood Cell Distribution Width with Poor Outcome in Pediatric Cardiac Surgery - A Retrospective Observational Study.

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) is a valuable indicator for evaluating inflammatory response and red blood cell distribution width (RBDW), a routinely available biomarker of likely erythropoietic dysfunction, which may be associated with adverse outcomes after cardiac surgery. This study aimed to investigate the association between these two readily available haematological parameters, with the poor outcomes in paediatric patients undergoing cardiac surgery. METHODS: A comprehensive review of medical records for paediatric patients who underwent cardiac surgery at our tertiary care centre between April 2022 and June 2023 was carried out. RBDW and NLR values were collected from complete blood count reports obtained on admission to the ICU. Demographic data, surgical details, and postoperative complications were also recorded. A receiver operating characteristic (ROC) curve and multivariable logistic regression were applied to identify the prognosis performance of preoperative NLR and RBDW for poor outcomes. RESULTS: The study included 219 patients meeting the inclusion criteria of which a total of 90 (41%) children experienced at least one of the poor outcomes. Preoperative NLR (AUC=0.88, 95%CI 0.36-0.70, cut off- 4.2) and RBDW (AUC=0.88, 95%CI 0.39-0.73, cut off- 18.5%) showed prognostic significance in the perioperative period. CONCLUSION: This retrospective observational study highlights a significant association between elevated Red Blood Cell Distribution Width (RBDW) and Neutrophil Lymphocyte Ratio (NLR) values and poor outcomes in paediatric patients undergoing cardiac surgery. These readily available haematological parameters could serve as potential prognostic indicators for identifying patients at risk of poor outcomes.

Stage-specific GATA3 induction promotes ILC2 development after lineage commitment.

Group 2 innate lymphoid cells (ILC2s) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 is a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains unclear. Herein, we identify ILC2-specific GATA3-related tandem super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 deficiency in the bone marrow, lung, liver, and small intestine with minimal impact on other ILC lineages or Th2 cells. Single-cell RNA-sequencing and subsequent flow cytometry analysis show that GATA3 induction mechanism, which is required for entering the ILC2 stage, is lost in IL-17RB+PD-1- late ILC2-committed precursor stage in G3SE-deficient mice. Cnot6l, part of the CCR4-NOT deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings implicate a stage-specific regulatory mechanism for GATA3 expression during ILC2 development.

Association between lymphocyte-to-monocyte ratio and prostate cancer in men: A population-based study.

Using the novel inflammatory biomarker lymphocyte-to-monocyte ratio (LMR), this work aimed to look into any potential connections between LMR and prostate cancer (PCa). A cross-sectional research investigation was conducted on 7706 male participants involved in the National Health and Nutrition Examination Survey from 2001 to 2010. Multivariate logistic regression modeling investigated the relationship between LMR levels and PCa risk. Furthermore, threshold analysis, subgroup analysis, interaction testing, and smoothed curve fitting were carried out. A significant negative correlation was seen between LMR and PCa risk (OR = 0.79, 95% CI: 0.65-0.97, P = .0002), even after controlling for potential confounding factors. A significant nonlinear negative correlation with a threshold effect and a breakpoint of 4.86 was found by smooth curve fitting between LMR and PCa. Subgroup analysis revealed a significant interaction (P for interaction = 0.0448) between the negative correlation between PCa and LMR about hypertension. Moreover, additional stratified smoothed curve fitting demonstrated a statistically significant inverse relationship between PCa risk and LMR. According to our findings, there is a substantial inverse relationship between PCa risk and LMR level. The inflammatory response-related index is quick, easy to use, and offers some clinical references. However, more extensive prospective investigations are required to confirm the involvement of LMR levels in PCa.

Biomarkers to predict efficacy of immune checkpoint inhibitors in colorectal cancer patients: a systematic review and meta-analysis.

Immune checkpoint inhibitors (ICIs) are approved to treat colorectal cancer (CRC) with mismatch-repair gene deficiency, but the response rate remains low. Value of current biomarkers to predict CRC patients' response to ICIs is unclear due to heterogeneous study designs and small sample sizes. Here, we aim to assess and quantify the magnitude of multiple biomarkers for predicting the efficacy of ICIs in CRC patients. We systematically searched MEDLINE, Embase, the Cochrane Library, and Web of Science databases (to June 2023) for clinical studies examining biomarkers for efficacy of ICIs in CRC patients. Random-effect models were performed for meta-analysis. We pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) for biomarkers predicting response rate and survival. 36 studies with 1867 patients were included in systematic review. We found that a lower pre-treatment blood neutrophil-to-lymphocyte ratio (n=4, HR 0.37, 95%CI 0.21-0.67) predicts good prognosis, higher tumor mutation burden (n=10, OR 4.83, 95%CI 2.16-10.78) predicts response to ICIs, and liver metastasis (n=16, OR 0.32, 95%CI 0.16-0.63) indicates resistance to ICIs, especially when combined with VEGFR inhibitors. But the predictive value of tumor PD-L1 expression (n=9, OR 1.01, 95%CI 0.48-2.14) was insignificant in CRC. Blood neutrophil-to-lymphocyte ratio, tumor mutation burden, and liver metastasis, but not tumor PD-L1 expression, function as significant biomarkers to predict efficacy of ICIs in CRC patients. These findings help stratify CRC patients suitable for ICI treatments, improving efficacy of immunotherapy through precise patient management. (PROSPERO, CRD42022346716).

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.

Neutrophil-Lymphocytes Ratio as Potential Early Marker for Alzheimer's Disease.

Background: Neutrophil-lymphocyte ratio (NLR) is a noninvasive, inexpensive, and easily applicable marker of inflammation. Since immune dysregulation leading to inflammation is regarded as a hallmark of dementia, in particular Alzheimer's disease (AD), we decided to investigate the potentials of NLR as a diagnostic and predictive biomarker in this clinical setting. Materials and Methods: NLR was measured in the blood of patients with AD (n = 103), amnestic type mild cognitive impairment (aMCI, n = 212), vascular dementia (VAD, n = 34), and cognitively healthy Controls (n = 61). One hundred twelve MCI patients underwent a regular clinical follow-up. Over a 36-months median follow-up, 80 remained stable, while 32 progressed to overt dementia. Results: NLR was higher in patients with aMCI or dementia compared to Controls; however, the difference was statistically significant only for aMCI (+13%, p=0.04) and AD (+20%, p=0.03). These results were confirmed by multivariate logistic analysis, which showed that high NLR was associated with an increase in the likelihood of receiving a diagnosis of aMCI (odd ratio (OR): 2.58, 95% confidence interval (CI): 1.36-4.89) or AD (OR: 3.13, 95%CI: 1.47-6.70), but not of VAD. NLR did not differ when comparing stable vs. progressing aMCI. Conclusions: This is the first report showing that NLR is significantly increased in MCI and AD but not in VAD. We also found that NLR was unable to predict the conversion from aMCI to AD. Further research on larger cohorts is warranted to definitely ascertain the application of NLR as a possible marker for aMCI and AD.

[Computer morphometry of peripheral blood lymphocytes in elderly patients with chronic pyelonephritis.]

The aim of the study was to investigate the peculiarities of morphometric parameters of peripheral blood lymphocytes in chronic pyelonephritis in elderly patients in comparison with young and middle-aged patients. A total of 81 patients with chronic pyelonephritis in the exacerbation phase were examined. All patients were divided into three age groups according to WHO recommendations: the 1st - 42patients of young age (18-44 years); the 2nd - 17 patients of middle age (45-59 years); the 3rd - 22 elderly patients (60-74 years). Computer morphometry of lymphocytes was performed in all examined patients. In elderly patients with chronic pyelonephritis the size and сytoplasmic-nuclear ratio of lymphocytes increase. This indicates the preservation of lymphocyte defense responses at this age. In male patients with chronic pyelonephritis in the 1st and 2nd age groups the size of lymphocytes increases, and in female patients - decreases. The сytoplasmic-nuclear ratio increases in males of these age groups, while it remains unchanged or decreases in females. Indirect indications of reduced immunity in young and middle-aged women with chronic inflammation in the kidneys have been obtained.

Elevated neutrophil-to-lymphocyte ratio combined with decreased lymphocyte-to-monocyte ratio is associated with increased peripheral airway resistance in patients with hepatic steatosis.

Although the link between hepatic steatosis and lung function has been confirmed, the focus has largely been on central airways. The association between hepatic steatosis and increased peripheral airway resistance has not yet been explored. Hepatic steatosis and increased peripheral resistance are connected with immunity dysregulation. High neutrophil-to-lymphocyte ratio (NLR) and low lymphocyte-to-monocyte ratio (LMR) have been recognized as indicators of immunity dysregulation. In this study, the association between hepatic steatosis and increased peripheral airway resistance was evaluated, and the effect of immunity dysregulation (high NLR/low LMR) on the increased peripheral airway resistance among patients with hepatic steatosis was explored. In this retrospective study, chest or abdomen CT scans and spirometry/impulse oscillometry (IOS) from 2018 to 2019 were used to identify hepatic steatosis and increased central/peripheral airway resistance in patients. Among 1391 enrolled patients, 169 (12.1%) had hepatic steatosis. After 1:1 age and abnormal ALT matching was conducted, clinical data were compared between patients with and without hepatic steatosis. A higher proportion of patients with hepatic steatosis had increased peripheral airway resistance than those without hepatic steatosis (52.7% vs 40.2%, P = .025). Old age, high body mass index, history of diabetes, and high NLR/low LMR were significantly correlated with increased peripheral airway resistance. The presence of hepatic steatosis is associated with increased peripheral airway. High NLR/low LMR is an independent associated factor of increased peripheral airway resistance in patients with hepatic steatosis. It is advisable for patients with hepatic steatosis to regularly monitor their complete blood count/differential count and undergo pulmonary function tests including IOS.

Airways epithelial exposure to Streptococcus pneumoniae in the presence of the alarmin IL-33 induces a novel subset of pro-inflammatory ILC2s promoting a mixed inflammatory response.

BACKGROUND: We have previously shown that asthma-like airways inflammation may be induced by topical exposure to respiratory tract pathogens such as S. pneumoniae (SP) in concert with epithelial alarmins such as IL-33. Details of the pathogenesis of this murine surrogate remain however unexplored. METHODS: Airways inflammation was induced by repeated, intranasal exposure of Il-4-/-, Rag1-/- and Rag2-/-Il2rg-/- mice (in which B lymphocyte IgE switching, adaptive and innate immunity are respectively ablated) as well as wild type mice to inactivated SP, IL-33 or both. Airways pathological changes were analysed, and the subsets and functions of locally accumulated ILC2s investigated by single cell RNA sequencing and flow cytometry. RESULTS: In the presence of IL-33, repeated exposure of the airways to inactivated SP caused marked eosinophil- and neutrophil-rich inflammation and local accumulation of ILC2s, which was retained in the Il-4-/- and Rag1-/- deficient mice but abolished in the Rag2-/-Il2rg-/- mice, an effect partly reversed by adoptive transfer of ILC2s. Single cell sequencing analysis of ILC2s recruited following SP and IL-33 exposure revealed a Klrg1+Ly6a+subset, expressing particularly elevated quantities of the pro-inflammatory cytokine IL-6, type 2 cytokines (IL-5 and IL-13) and MHC class II molecules, promoting type 2 inflammation as well as involved in neutrophil-mediated inflammatory responses. CONCLUSION: Local accumulation of KLRG1+Ly6a+ ILC2s in the lung tissue is a critical aspect of the pathogenesis of airways eosinophilic and neutrophil-rich inflammation induced by repeated exposure to SP in the presence of the epithelial alarmin IL-33.

CTLA-4-expressing ILC3s restrain interleukin-23-mediated inflammation.

Interleukin (IL-)23 is a major mediator and therapeutic target in chronic inflammatory diseases that also elicits tissue protection in the intestine at homeostasis or following acute infection1-4. However, the mechanisms that shape these beneficial versus pathological outcomes remain poorly understood. To address this gap in knowledge, we performed single-cell RNA sequencing on all IL-23 receptor-expressing cells in the intestine and their acute response to IL-23, revealing a dominance of T cells and group 3 innate lymphoid cells (ILC3s). Unexpectedly, we identified potent upregulation of the immunoregulatory checkpoint molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) on ILC3s. This pathway was activated by gut microbes and IL-23 in a FOXO1- and STAT3-dependent manner. Mice lacking CTLA-4 on ILC3s exhibited reduced regulatory T cells, elevated inflammatory T cells and more-severe intestinal inflammation. IL-23 induction of CTLA-4+ ILC3s was necessary and sufficient to reduce co-stimulatory molecules and increase PD-L1 bioavailability on intestinal myeloid cells. Finally, human ILC3s upregulated CTLA-4 in response to IL-23 or gut inflammation and correlated with immunoregulation in inflammatory bowel disease. These results reveal ILC3-intrinsic CTLA-4 as an essential checkpoint that restrains the pathological outcomes of IL-23, suggesting that disruption of these lymphocytes, which occurs in inflammatory bowel disease5-7, contributes to chronic inflammation.

Transcriptomic diversity of innate lymphoid cells in human lymph nodes compared to BM and spleen.

Innate lymphoid cells (ILCs) are largely tissue-resident, mostly described within the mucosal tissues. However, their presence and functions in the human draining lymph nodes (LNs) are unknown. Our study unravels the tissue-specific transcriptional profiles of 47,287 CD127+ ILCs within the human abdominal and thoracic LNs. LNs contain a higher frequency of CD127+ ILCs than in BM or spleen. We define independent stages of ILC development, including EILP and pILC in the BM. These progenitors exist in LNs in addition to naïve ILCs (nILCs) that can differentiate into mature ILCs. We define three ILC1 and four ILC3 sub-clusters in the LNs. ILC1 and ILC3 subsets have clusters with high heat shock protein-encoding genes. We identify previously unrecognized regulons, including the BACH2 family for ILC1 and the ATF family for ILC3. Our study is the comprehensive characterization of ILCs in LNs, providing an in-depth understanding of ILC-mediated immunity in humans.

Predicting prognosis in colorectal cancer patients with curative resection using albumin, lymphocyte count and RAS mutations.

Colorectal cancer (CRC) poses a significant global health challenge, demanding reliable prognostic tools to guide treatment decisions. This study introduces a novel prognostic scoring system, the albumin-total lymphocyte count-RAS index (ALRI), integrating serum albumin, lymphocyte count, and RAS gene mutations. A cohort of 445 stage I-III CRC patients undergoing curative resection was analyzed, revealing ALRI's association with clinicopathological factors, including age, tumor location, and invasion depth. The ALRI demonstrated superior prognostic value, with a cutoff value of 2 distinguishing high and low-risk groups. The high-ALRI group exhibited elevated rates of recurrence. Univariate and multivariate analyses identified ALRI as an independent predictor for both 5 year recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier curves illustrated significant differences in RFS and OS between high and low-ALRI groups, emphasizing ALRI's potential as a prognostic marker. Importantly, ALRI outperformed existing nutritional indices, such as controlling nutritional status and neutrophil-to-lymphocyte ratio, in predicting overall survival. The study underscores the comprehensive insight provided by ALRI, combining inflammatory, nutritional, and genetic information for robust prognostication in CRC patients. This user-friendly tool demonstrates promise for preoperative prognosis and personalized treatment strategies, emphasizing the crucial role of inflammation and nutrition in CRC outcomes.