Bone morphogenetic protein 4 inhibits corneal neovascularization by blocking NETs-induced disruption to corneal epithelial barrier.

Corneal neovascularization (CoNV) is the second leading cause of visual impairment worldwide, and current drugs have certain limitations. Inflammatory response is the core pathological process of CoNV. Neutrophil extracellular traps (NETs) are generated after neutrophil activation, which promotes neovascularization. Prior studies demonstrated that bone morphogenetic protein 4 (BMP4) could significantly reduce inflammation and CoNV formation, its exact molecular mechanism remains unclear. Therefore, we stimulated human peripheral blood neutrophils with phorbol myristate acetate (PMA) or deoxyribonuclease I (DNase I) to induce or inhibit NETs formation. By using corneal sutures and subconjunctival injections of NETs or DNase I, rat CoNV models were established. Compared with the suture group, NETs formation and inflammatory cell infiltration in the corneal stroma were significantly increased, corneal edema was aggravated, and the length, area and diameter of CoNV were significantly enhanced in the NETs group. Furthermore, by curetting the corneal epithelial apical junctional complexes (AJCs), a crucial component in preserving the function of the corneal epithelial barrier, we discovered that the damage of AJCs had a significant role in inducing CoNV formation. NETs could induce CoNV formation by injuring corneal epithelial AJCs. Finally, by comparing the aforementioned indicators after the intervention of BMP4, BMP4 inhibitor Noggin and NADPH oxidase (NOX) inhibitor, we finally demonstrated that BMP4 could inhibit NETs-induced inflammation and corneal epithelial AJC injury, repair corneal epithelial barrier function and eventually inhibit CoNV formation by blocking NOX-2-dependent NETs formation.

Predictive values and relationships of serum PSA levels, delta neutrophil index, neutrophil-lymphocyte ratio and other hematological parameters in patients with acute prostatitis.

BACKGROUND: This study aimed to evaluate the predictive values and relationships of serum prostate-specific antigen (PSA) levels, delta neutrophil index (DNI), neutrophil-lymphocyte ratio (NLR), and other hematological parameters in patients diagnosed with acute prostatitis. METHODS: Serum PSA levels and hemogram parameters of patients diagnosed with acute prostatitis were retrospectively analyzed. Healthy patients of the same age group were assigned to the control group. WBC, neutrophil, lymphocyte, thrombocyte (PLT), mean platelet volume (MPV), plateletcrit (PCT), NLR, and DNI were determined. Serum total PSA and C-reactive protein (CRP) levels were also assessed. RESULTS: Total PSA levels (3.48 [1.11-6.66]) in the acute prostatitis (AP) group were significantly higher than those of healthy men (0.82 [0.47-1.39]) (p < 0.001). Total CRP levels (3.88 [1.50-22.03]) in the AP group were significantly higher than those in healthy men (1.15 [0.89-2.00]) (p < 0.001). The sensitivity and specificity of PSA at a cutoff value of 1.52 were 68.4% and 79.7%, respectively. The NLR value in the AP group was 2.62 (1.87-4.42), compared to 1.63 (1.18-2.20) in the healthy group (p < 0.001). Differences in WBC, neutrophil, and lymphocyte counts were also statistically significant (p < 0.001). There were no significant differences in PLT, PCT, or DNI values. Significant positive correlations were observed between PSA, CRP, and DNI values (all p < 0.001). CONCLUSION: This study demonstrated the usefulness of NLR, PSA, CRP, and WBC as predictors of acute prostatitis. NLR is a simple, inexpensive inflammation parameter that correlates well with CRP levels.

Hydrogen-releasing Magnesium Hydrogel Mitigates Post Laminectomy Epidural Fibrosis through Inhibition of Neutrophil Extracellular Traps.

Epidural fibrosis is a primary contributor to the failure of laminectomy surgeries, leading to the development of failed back surgery syndrome (FBSS). Post-laminectomy, neutrophils infiltrate the surgical site, generating neutrophil extracellular traps (NETs) that contribute to epidural fibrosis. Reactive oxygen species (ROS) play a pivotal role in mediating NETs formation. Molecular hydrogen, recognized for its selective antioxidant properties and biosafety, emerges as a potential therapeutic gas in suppressing epidural fibrosis. In this study, we developed an in-situ hydrogen release hydrogel that inhibits the formation of NETs and mitigates epidural scarring. Biodegradable magnesium (Mg) microspheres served as a hydrogen source, coated with PLGA to regulate hydrogen release. These microspheres (Mg@PLGA) were then incorporated into a PLGA-PEG-PLGA thermosensitive hydrogel (Mg@PLGA@Gel), providing a surgical implant for sustained, long-term hydrogen release. In vitro experiments confirmed the biocompatibility of the system, demonstrating that hydrogen produced by Mg@PLGA effectively neutralizes neutrophil intracellular ROS and inhibits NETs formation. Histological analyses, including H&E staining, MRI, Masson staining, and immunohistochemistry, collectively indicate that Mg@PLGA@Gel is biocompatible and effectively inhibits epidural fibrosis post-laminectomy. Furthermore, Mg@PLGA@Gel inhibits ROS accumulation and NETs formation at the surgical site. These findings suggest that Mg@PLGA@Gel ensures continuous, therapeutic hydrogen concentration, providing relief from epidural fibrosis in a laminectomy mouse model. STATEMENT OF SIGNIFICANCE: •The hydrogen-releasing hydrogel combines the therapeutic effects of a physical barrier with immunomodulation. •In situ-generated molecular hydrogen scavenges ROS caused by surgical stress and suppresses NETs formation. •The hydrogen-releasing hydrogel is demonstrated to exhibit high biocompatibility and inhibit epidural scar formation in vivo.

Potential prognostic predictors of treatment with immune checkpoint inhibitors for advanced endometrial cancer.

BACKGROUND: Prognostic predictors of immunotherapy in patients with advanced endometrial cancer remain unclear. The potential role of inflammatory predictors, including pretreatment neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and hemoglobin, albumin, lymphocyte and platelet scores, was investigated. METHODS: Between August 2018 and December 2023, 35 patients were retrospectively analyzed. Prognostic predictors were compared, and optimal cut-off values that exhibited the greatest discrimination for overall response, disease control, progression-free survival and overall survival were determined. Multivariate analysis was used to assess the prognostic significance of the predictors. RESULTS: The greatest discrimination for overall response, progression-free survival and overall survival included platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio and hemoglobin, albumin, lymphocyte and platelet; the areas under the curve were 0.638, 0.649 and 0.641, respectively. The precise cut-off values of neutrophil-to-lymphocyte ratio for progression-free survival and overall survival were 4.92 and 5.40, respectively. The lower neutrophil-to-lymphocyte ratio group had a significantly longer progression-free survival (P = 0.001, median survival; 4.0 months vs. 19 months) and longer overall survival (P = 0.002, median survival; 5.0 months vs. 21 months). Of the risk factors assessed, neutrophil-to-lymphocyte ratio (hazard ratio = 4.409; 95% CI = 1.10-17.64; P = 0.036) and regimen (hazard ratio = 5.559; 95% CI = 1.26-24.49; P = 0.023) were independently correlated with overall survival. CONCLUSION: In patients with advanced endometrial cancer, pretreatment neutrophil-to-lymphocyte ratio may be a prognostic predictor of those who would benefit from immunotherapy.

A novel prognosis evaluation indicator of patients with sepsis created by integrating six microfluidic-based neutrophil chemotactic migration parameters.

Impaired neutrophil migration in sepsis is associated with a poor prognosis. The potential of utilizing neutrophil chemotaxis to assess immune function, disease severity, and patient prognosis in sepsis remains underexplored. This study employed an innovative approach by integrating a multi-tip pipette with a Six-Unit microfluidic chip (SU6-chip) to establish gradients in six microchannels, thereby analyzing neutrophil chemotaxis in sepsis patients. We compared chemotactic parameters between healthy controls (NH = 20) and sepsis patients (NS1 = 25), observing significant differences in gradient perception time (GP), migration distance (MD), peak velocity (Vmax), chemotactic index (CI), reverse migration rate (RM), and stop migration number (SM). A novel composite indicator, the Sepsis Neutrophil Migration Evaluation (SNME) index, was developed by integrating these six chemotactic migration parameters. The SNME index and individual chemotaxis parameters showed significant correlations with the Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE II) score, hypersensitivity C-reactive protein (hs-CRP), and heparin-binding protein (HBP). Moreover, the SNME index demonstrated potential for monitoring sepsis progression, with ROC analysis confirming its predictive accuracy (area under the curve [AUC] = 0.895, cutoff value = 31.5, specificity = 86.73 %, sensitivity = 86.71 %), outperforming individual neutrophil chemotactic parameters. In conclusion, the SNME index represents a promising new tool for adjunctive diagnosis and prognosis assessment in patients with sepsis.

Effect of oxymatrine on neutrophil function based on zebrafish inflammation model and primary neutrophil inflammatory responses.

Sophora flavescens Ait. (SFA), an extensively utilized herb for the treatment of fevers, inflammatory disorders, ulcers and skin diseases related to bur, contains oxymatrine (OMT) as its principal active constituent. OMT exerts regulatory effects over inflammation, oxidative stress and apoptosis. Neutrophils, critical regulators of the inflammation response, have not been thoroughly elucidated regarding the protective properties and underlying mechanisms of OMT-mediated anti-inflammation. This study was aim to explore the protective effect of OMT on neutrophils under inflammatory conditions and delve into its potential mechanism. Leveraging the advantages of zebrafish, an animal model with a real-time dynamic observation system, we established an in vivo caudal fin wound model and a copper sulfate induced-inflammation model in zebrafish line Tg (mpx:GFP). The result revealed that OMT significantly attenuated neutrophil migration, upregulated the mRNA expression levels of JNK, casp3, mapk14a, mapkapk2a and map2k1 damaged by zebrafish caudal fin wound model, and downregulated mRNA expression levels of JNK, casp3, mapk14a, mapkapk2a and map2k1 in the copper sulfate injury model. In vitro experiments demonstrated that OMT modulated the chemotaxis response of primary neutrophils from mice, enhanced phagocytosis, reduced oxidative stress and alleviated inflammation level. We hypothesize that the OMT may exert its anti-inflammatory effects by regulating primary neutrophils through the MAPK signaling pathway.

Inflammatory cytokine signalling in vulvovaginal candidiasis: a hot mess driving immunopathology.

Protective immunity to opportunistic fungal infections consists of tightly regulated innate and adaptive immune responses that clear the infection. Immune responses to infections of the vaginal mucosa by Candida species are, however, an exception. In the case of vulvovaginal candidiasis (VVC), the inflammatory response is associated with symptomatic disease, rather than that it results in pathogen clearance. As such VVC can be considered an inflammatory disease, which is a significant public health problem due to its predominance as a female-specific fungal infection. Particularly, women with recurrent VVC (RVVC) suffer from a significant negative impact on their quality of life and mental health. Knowledge of the inflammatory pathogenesis of (R)VVC may guide more effective diagnostic and therapeutic options to improve the quality of life of women with (R)VVC. Here, we review the immunopathogenesis of (R)VVC describing several elements that induce an inflammatory arson, starting with the activation threshold established by vaginal epithelial cells that prevent unnecessary ignition of inflammatory responses, epithelial and inflammasome-dependent immune responses. These inflammatory responses will drive neutrophil recruitment and dysfunctional neutrophil-mediated inflammation. We also review the, sometimes controversial, findings on the involvement of adaptive and systemic responses. Finally, we provide future perspectives on the potential of some unexplored cytokine axes and discuss whether VVC needs to be subdivided into subgroups to improve diagnosis and treatment.

The impact of donor-specific antibodies' presence on the outcome post-allogeneic hematopoietic stem cell transplantation: a survey from a single center.

Introduction: Donor-specific antibodies (DSAs) correspond to anti-HLA antibodies of the recipient that are specifically directed to a mismatched antigen of the donor. In the setting of solid organ transplantation DSAs are associated with rejection. Their role is still debated in allogeneic cell transplantation. International guidelines recommend testing patients for DSA before transplant, and if possible, choosing a donor with negative screening. Methods: We collected clinical data of 236 recipients of alloSCT, performed at our institution from March 2019 to October 2023, to evaluate their impact on engraftment. Serum from all patients was tested for DSA. Results: 186 patients (79%) achieved sustained myeloid engraftment within day 30 post alloSCT. Thirty-two out 236 (13%) patients engrafted after day 30 post alloSCT. The median times to neutrophil engraftment and platelet engraftment were respectively 21 days (range 11-121 days) and 19 days (range 10-203 days). Fourteen out 236 patients (6%) experienced PrGF. .Twenty-nine patients (12 %) were DSA-positive. Among 29 patients with DSA positivity, 17 had a haploidentical donor and 12 had a UD donor. DSA positivity directly correlates respectively with neutrophil and platelets engraftment failure at 30 days after alloSCT (p=0.01 and p= 0.0004). Univariate Cox analysis showed that factors, including DSAs positivity, disease type, disease status, donor type, conditioning regimen, patient's age, and CD34+ were correlated with neutrophil and platelet engraftment failure at 30 days after alloSCT. Younger patients with DSA negativity, with acute leukemia, in complete response at the time of transplant, who received a higher dose of CD34+ cells from a sibling donor after a myeloablative conditioning regimen, have a reduced risk of neutrophil and platelet engraftment failure at day +30 post alloSCT.Multivariate analysis confirmed the impact of the presence of DSA only for platelet engraftment, confirming the role of type and status disease, donor type, recipient age, and CD34+ cells infused on engraftment. DSA presence has no impact on TRM, DFS, and OS. Discussion: PrGF has a multifactorial pathogenesis, where DSA is not the only player, but its impact could vary depending on the transplant platform. Thus patient screening may be helpful to choose the best donor and transplant strategy.

Neutrophil-to-lymphocyte ratio as a predictor of all-cause and cardiovascular mortality in coronary heart disease and hypertensive patients: a retrospective cohort study.

Background: To date, no studies have investigated the correlation between the neutrophil-to-lymphocyte ratio (NLR) and the long-term risk of mortality in individuals with both coronary heart disease (CHD) and hypertension. This study aims to evaluate the association between NLR and all-cause and cardiovascular mortality among this patient population. Methods: National Death Index (NDI) and National Health and Nutrition Examination Survey (NHANES 2001-2018) were the data sources. A nonlinear association between the NLR and mortality risk was shown by restricted cubic spline (RCS) analysis. Using a weighted Cox proportional hazards model, we quantitatively evaluated the effect of NLR on mortality risk.The capacity of NLR to forecast survival was assessed by evaluating time-dependent receiver operating characteristic (ROC) curves. A mediating influence analysis was conducted to assess the influence of NLR on mortality through eGFR as a mediator. Results: The study involved a total of 2136 individuals. During the median follow-up interval of 76.0 months, 801 deaths were recorded. The RCS analysis showed NLR and mortality risk to have a nonlinear relationship. Two groups were established based on the participants' NLR levels: a group with high NLR (NLR > 2.65) and a group with low NLR (NLR < 2.65). After adjusting for potential confounding factors, the Cox proportional hazards model revealed that participants with an increased NLR faced a significantly higher risk of cardiovascular mortality. (HR 1.58, 95% CI 1.33-1.82, p < 0.0001) and all-cause mortality (HR 1.46, 95% CI 1.30-1.62, p < 0.0001). An analysis of interactions and data stratification corroborated the validity of our findings. eGFR was identified as a partial mediator in the association between NLR and mortality rates, contributing 12.17% and 9.66% of the variance in all-cause and cardiovascular mortality, respectively. The predictive performance for cardiovascular mortality was quantified using ROC curves, with respective AUC values of 0.67, 0.65, and 0.64 for predictions over 3, 5, and 10 years. The AUC values for all-cause mortality were 0.66, 0.64, and 0.63 for the same time frames. Conclusion: For patients with CHD and hypertension, an elevated NLR serves as an independent prognostic indicator for both all-cause and cardiovascular mortality.

Prospective nutrition-inflammation markers for predicting early stoma-related complications in patients with colorectal cancer undergoing enterostomy.

Background: Enterostomy is important for radical resection of colorectal cancer (CRC). Nevertheless, the notable occurrence of complications linked to enterostomy results in a reduction in patients' quality of life and impedes adjuvant therapy. This study sought to forecast early stoma-related complications (ESRCs) by leveraging easily accessible nutrition-inflammation markers in CRC patients. Methods: This study involved 470 individuals with colorectal cancer who underwent intestinal ostomy at Changhai Hospital Affiliated with Naval Medical University as the internal cohort. Between January 2016 and December 2018, the patients were enrolled and randomly allocated into a primary training group and a secondary validation group, with a ratio of 2:1 being upheld. The research encompassed collecting data on each patient's clinical and pathological status, along with preoperative laboratory results. Independent risk factors were identified through Lasso regression and multivariate analysis, leading to the development of clinical models represented by a nomogram. The model's utility was assessed using decision curve analysis, calibration curve, and ROC curve. The final model was validated using an external validation set of 179 individuals from January 2015 to December 2021. Results: Among the internal cohort, stoma complications were observed in 93 cases. Multivariate regression analysis confirmed that age, stoma site, and elevated markers (Mon, NAR, and GLR) in conjunction with diminished markers (GLB and LMR) independently contributed to an increased risk of ESRCs. The clinical model was established based on these seven factors. The training, internal, and external validation groups exhibited ROC curve areas of 0.839, 0.812, and 0.793, respectively. The calibration curve showed good concordance among the forecasted model with real incidence of ostomy complications. The model displayed outstanding predictive capability and is deemed applicable in clinical settings, as evidenced by Decision Curve Analysis. Conclusion: This study identified nutrition-inflammation markers (GLB, NAR, and GLR) in combination with demographic data as crucial predictors for forecasting ESRCs in colorectal cancer patients. A novel prognostic model was formulated and validated utilizing these markers.

The relationship of COVID-19 severity with laboratory findings and neutrophil-to-lymphocyte ratio in patients admitted to a large teaching hospital in Iran: A cross-sectional study.

Background and Aims: COVID-19 patients might be admitted to the hospital based on their clinical manifestations or to the intensive care unit (ICU) due to the severity of their symptoms or critical situation. Our main objective was to investigate clinical and demographic factors influencing COVID-19 patients' admission to the ICU and length of stay (LOS) using extracted data from the hospital information systems in Iran. Methods: The data of hospitalized patients with confirmed COVID-19 were retrieved from the health information system of Imam Khomeini Hospital Complex, Tehran, Iran between March 2020 and February 2022. The primary outcome was the ICU admission, and the secondary outcome was the LOS. The correlation analysis between laboratory findings and demographic data with ICU admission and LOS was done using SPSS 21.0, and p < 0.05 was considered significant. Results: Of all the 4156 patients, 2391 (57.5%) were male and the mean age was 58.69 ± 8.19 years. Of these, 9.5% of patients were admitted to ICU at any time point during their hospital stay. Age and laboratory variables such as neutrophil-to-lymphocyte ratio (NLR), ALT (U/L), albumin (g/dL), plasma glucose (mg/dL), ferritin levels (ng/mL), and phosphorous levels (mg/dL) shown the significant relationship with ICU admission. Also, being a smoker and having hypoxemia had a significant relationship with longer stays in the hospital. In this study, we validated a cut-off value of 4.819 for NLR, calculated at hospitalization, as a useful predictor of disease progression and occurrence of serious clinical outcomes, such as ICU admission. Conclusion: The study examined various clinical factors associated with ICU admission in COVID-19 patients. The findings suggest that certain factors can increase the risk of ICU admission and influence the length of hospital stay which should be focused in future studies.

Flagellum-deficient Pseudomonas aeruginosa is more virulent than non-motile but flagellated mutants in a cystic fibrosis mouse model.

Loss of the flagellum marks the pathoadaptation of Pseudomonas aeruginosa to the cystic fibrosis (CF) airway environment during lung disease. Losing the flagellum is advantageous to the bacterium as the flagellum can be recognized by immune cells. The primary purpose of the flagellum is, however, to provide motility to the bacterium. Our goal was to determine whether the loss of flagellar motility or the loss of flagellum expression contributes to P. aeruginosa lung infection in CF. To address this, wild-type and gut-corrected FABP-human cystic fibrosis transmembrane conductance regulator (hCFTR) mice deficient in the murine Cftr gene were infected intratracheally with lethal doses of wild-type or flagellum-deficient P. aeruginosa. While there was no significant difference in the survival of wild-type mice after infection with either of the bacterial strains, a significantly higher mortality was observed in FABP-hCFTR mice infected with flagellum-deficient P. aeruginosa, compared to mice infected with their flagellated counterparts. When FABP-hCFTR mice were infected with isogenic, motility-deficient flagellated mutants, animal survival and lung bacterial titers were similar to those observed in mice infected with the wild-type bacterium. Airway levels of neutrophils and the amount neutrophil elastase were similar in mice infected with either the wild-type bacteria or the flagellum-deficient P. aeruginosa. Our results show that FABP-hCFTR mice have a different response to flagellum loss in P. aeruginosa compared to wild-type animals. The loss of flagellum expression, rather than the loss of motility, is the main driver behind the increased virulence of flagellum-deficient P. aeruginosa in CF. These observations provide new insight into P. aeruginosa virulence in CF.IMPORTANCEPseudomonas aeruginosa, a major respiratory pathogen in cystic fibrosis, is known to lose its flagellum during the course of infection in the airways. Here, we show that the loss of flagellum leads to a more enhanced virulence in Cftr-deficient cystic fibrosis mice than in control animals. Loss of flagellum expression, rather than the loss of flagellar swimming motility, represents the main driver behind this increased virulence suggesting that this appendage plays a specific role in P. aeruginosa virulence in cystic fibrosis airways.

Determination of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index in dogs with leptospirosis.

Leptospirosis is a globally distributed zoonosis with multisystemic involvement in canine species, capable of causing a pulmonary hemorrhagic syndrome (LPHS) in the most severe cases. In humans, the neutrophil to lymphocyte ratio (NLR), platelets to lymphocytes (PLR) and systemic immune-inflammation index (SII) have been described as predictors of morbidity and mortality in various pathologies, but no such studies have been developed for canine leptospirosis. Hence, we aimed to assess the usefulness of NLR, PLR and SII in dogs affected with leptospirosis, focusing on those that died or survived after hospitalization, whether or not they developed LPHS. The leptospirosis group was composed by 36 dogs while the control group consisted of 32 healthy dogs. The NLR, associated with inflammation, demonstrated a threefold or greater increase in all leptospirosis groups compared to the control group (median 2.44 ± 1.66) (developing or not LPHS). Dogs that died (median 67.78 ± 158.67), developed LHPS (median 85.17 ± 143.77), or both developed LHPS and died (median 67.78 ± 155,14) had a lower PLR in comparison to the control group (median 101,82 ± 53,75) and the rest of groups, but no statistically significant differences were observed (p > 0.05). The SII was higher in leptospirosis-affected dogs that survived (median 1356,92 ± 2726,29) and statistically significant differences were observed in those who did not develop LPHS (median 1770,41 ± 2630,77; p < 0.05) compared to the control group (median 555,21 ± 313,26). Our data shows that NLR may be used as inflammation indicator, while more studies are needed for PLR and SII in canine leptospirosis.

The preoperative scoring system combining neutrophil/lymphocyte ratio and CA19-9 predicts the long-term prognosis of intrahepatic cholangiocarcinoma patients undergoing curative liver resection.

BACKGROUND: This study aims to investigate preoperative prognostic factors available for intrahepatic cholangiocarcinoma (ICC) patients and propose a new preoperative prognostic scoring system for ICC that combines CA19-9 and neutrophil/lymphocyte ratio (NLR). METHODS: In this retrospective analysis, 1728 patients diagnosed with ICC and undergoing curative liver resections were studied. This study employed univariate and multivariate Cox regression to find factors affecting recurrence and overall survival (OS), and furthermore assessed how preoperative models influenced tumor traits and postoperative recurrence. RESULTS: The results of the multivariate Cox regression analysis indicated that two preoperative variables, NLR and Ca19-9, were independent risk factors affecting postoperative recurrence and OS in ICC patients. Based on this data, assigning a score of 0 (NLR ≤ 2.4 and Ca19-9 ≤ 37U/ml) or 1 (NLR > 2.4 and Ca19-9 > 37U/ml) to these two factors, a preoperative prognostic score was derived. According to the scoring model, patients were divided into three groups: 0 points (low-risk group), 1 point (intermediate-risk group), and 2 points (high-risk group). The 5-year recurrence and OS rates for the three groups were 56.6%, 68.2%, 77.8%, and 56.8%, 40.6%, 27.6%, respectively, with all P values < 0.001. Furthermore, high-risk group patients were more prone to early recurrence (early recurrence rates for high-, intermediate-, and low-risk groups were 56.8%, 51.5%, and 37.1%, respectively, P < 0.001) and extrahepatic metastasis (extrahepatic metastasis rates for high-, intermediate-, and low-risk groups were 31.7%, 26.4%, and 15.4%, respectively, P < 0.001). In terms of tumor characteristics, high-risk group patients had larger tumor diameters and were more likely to experience microvascular invasion, lymph node metastasis, and perineural invasion. CONCLUSIONS: The predictive capacity of postoperative recurrence and OS rates in ICC patients is effectively captured by the preoperative scoring system incorporating NLR and CA19-9 levels.

SYK promotes the formation of neutrophil extracellular traps by inducing PKM2 nuclear translocation and promoting STAT3 phosphorylation to exacerbate hepatic ischemia-reperfusion injury and tumor recurrence.

BACKGROUND: At present, hepatic ischemia-reperfusion injury (IRI) is an important complication of partial hepatectomy and liver transplantation, and it is an important cause of poor prognosis. Spleen tyrosine kinase(SYK) plays an important role in a variety of signaling pathways in the liver, but its role in hepatic IRI is still unclear. This study aims to investigate the role and mechanism of SYK in hepatic IRI and tumor recurrence. METHODS: We first observed the activation of SYK in the liver of mice in response to hepatic IRI. Subsequently, Pharmacological inhibitions of SYK were used to evaluated the effect of SYK on neutrophil recruitment and NETosis, and further explored the effect of SYK on IRI and tumor recurrence. RESULTS: Our study shows that SYK is activated in response to hepatic IRI and aggravates liver injury. On the one hand, neutrophils SYK during the early stage of liver reperfusion increases neutrophil extracellular traps (NETs) production by promoting Pyruvate kinase M2(PKM2) nuclear translocation leading to upregulation of phosphorylated STAT3, thereby exacerbating liver inflammation and tumor recurrence. On the other hand, macrophages SYK can promote the recruitment of neutrophils and increase the activation of NLRP3 inflammasome and IL1ß, which further promotes the formation of NETs. CONCLUSIONS: Our study demonstrates that neutrophil and macrophage SYK synergistically promote hepatic IRI and tumor recurrence, and SYK may be a potential target to improve postoperative hepatic IRI and tumor recurrence.

Mitochondrial Plasticity and Glucose Metabolic Alterations in Human Cancer under Oxidative Stress-From Viewpoints of Chronic Inflammation and Neutrophil Extracellular Traps (NETs).

Oxidative stress elicited by reactive oxygen species (ROS) and chronic inflammation are involved both in deterring and the generation/progression of human cancers. Exogenous ROS can injure mitochondria and induce them to generate more endogenous mitochondrial ROS to further perpetuate the deteriorating condition in the affected cells. Dysfunction of these cancer mitochondria may possibly be offset by the Warburg effect, which is characterized by amplified glycolysis and metabolic reprogramming. ROS from neutrophil extracellular traps (NETs) are an essential element for neutrophils to defend against invading pathogens or to kill cancer cells. A chronic inflammation typically includes consecutive NET activation and tissue damage, as well as tissue repair, and together with NETs, ROS would participate in both the destruction and progression of cancers. This review discusses human mitochondrial plasticity and the glucose metabolic reprogramming of cancer cells confronting oxidative stress by the means of chronic inflammation and neutrophil extracellular traps (NETs).

Itaconate to treat acute lung injury: recent advances and insights from preclinical models.

Acute lung injury (ALI) is defined as the acute onset of diffuse bilateral pulmonary infiltration, leading to PaO2/FiO2 ≤ 300 mmHg without clinical evidence of left atrial hypertension. Acute respiratory distress syndrome (ARDS) involves more severe hypoxemia (PaO2/FiO2 ≤ 200 mmHg). Treatment of ALI and ARDS has received renewed attention as the incidence of ALI caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has increased. Itaconate and its derivatives have shown therapeutic potential against ALI. This review provides an in-depth summary of the mechanistic research of itaconate in the field of acute lung injury, including inducing autophagy, preventing ferroptosis and pyroptosis, shifting macrophage polarization to an anti-inflammatory M2 phenotype, inhibiting neutrophil activation, regulating epigenetic modifications, and repressing aerobic glycolysis. These compounds merit further consideration in clinical trials. We anticipate that the clinical translation of itaconate-based drugs can be accelerated.

HL-60 cells as a valuable model to study LPS-induced neutrophil extracellular traps release.

Neutrophil Extracellular Traps (NETs) present a paradoxical role in infectious diseases, contributing to both immunity and pathogenesis. The complex nature of this process necessitates further characterization to elucidate its clinical implications. However, studying NETs faces challenges with primary neutrophils due to their heterogeneity, short lifespan, and lack of adequate cryopreservation. Researchers often turn to alternative models, such as differentiated HL-60 cells (dHL-60). This study explored LPS-induced NETs formation in dHL-60 cells, revealing significant responses to LPS from Pseudomonas aeruginosa, although significantly lower than primary neutrophils. Moreover, Spleen Tyrosine Kinase (SYK) inhibition with R406, the active metabolite of the drug Fostamatinib, previously demonstrated to suppress NETs in primary neutrophils, effectively reduced NETs release in dHL-60 cells. dHL-60 cells, offering easier manipulation, consistent availability, and no donor variability in functional responses, possess characteristics suitable for high-throughput studies evaluating NETosis. Overall, dHL-60 cells may be a valuable in vitro model for deciphering the molecular mechanisms of NETosis in response to LPS, contributing to our available tools for understanding this complex immune process.

Efficacy and prognostic factors of stereotactic body radiotherapy combined with immunotherapy for pulmonary oligometastases: a preliminary retrospective cohort study.

Background: Stereotactic body radiotherapy (SBRT) combined immunotherapy has a synergistic effect on patients with stage IV tumors. However, the efficacy and prognostic factors analysis of SBRT combined immunotherapy for patients with pulmonary oligometastases have rarely been reported in the studies. The purpose of this study is to explore the efficacy and prognostic factors analysis of SBRT combined immunotherapy for patients with oligometastatic lung tumors. Methods: A retrospective analysis was conducted on 43 patients with advanced tumors who received SBRT combined with immunotherapy for pulmonary oligometastases from October 2018 to October 2021. Local control (LC), progression-free survival (PFS), and overall survival (OS) were assessed using the Kaplan-Meier method. Univariate and multivariate analyses of OS were performed using the Cox regression model, and the P value <0.05 was considered statistically significant. The receiver operating characteristic (ROC) curve of neutrophil-to-lymphocyte ratio (NLR) after SBRT was generated. Spearman correlation analysis was used to determine the relationship of planning target volume (PTV) with absolute lymphocyte count (ALC) before and after SBRT and with neutrophil count (NE) after SBRT. Additionally, linear regression was used to examine the relationship between ALC after SBRT and clinical factors. Results: A total of 43 patients with pulmonary oligometastases receiving SBRT combined with immunotherapy were included in the study. The change in NLR after SBRT was statistically significant (P<0.001). At 1 and 2 years, respectively, the LC rates were 90.3% and 87.5%, the OS rates were 83.46% and 60.99%, and the PFS rates were 69.92% and 54.25%, with a median PFS of 27.00 (17.84-36.13) months. Univariate and multivariate Cox regression analyses showed that a shorter interval between radiotherapy and immunization [≤21 days; hazard ratio (HR) =1.10, 95% confidence interval (CI): 0.06-0.89; P=0.02] and a low NLR after SBRT (HR =0.24, 95% CI: 1.01-1.9; P=0.03) were associated with improved OS. The ROC curve identified 4.12 as the cutoff value for predicting OS based on NLR after SBRT. NLR after SBRT ≤4.12 significantly extended OS compared to NLR after SBRT >4.12 (log-rank P=0.001). Spearman correlation analysis and linear regression analysis showed that PTV was negatively correlated with ALC after SBRT. Conclusions: Our preliminary research shows that SBRT combined with immunotherapy has a good effect, and NLR after SBRT is a poor prognostic factor for OS. Larger PTV volume is associated with decreased ALC after SBRT.

Prognostic role of dynamic changes in inflammatory indicators in patients with non-small cell lung cancer treated with immune checkpoint inhibitors-a retrospective cohort study.

Background: Immune checkpoint inhibitors (ICIs) have become one of the standard treatments for non-small cell lung cancer (NSCLC) patients without driver mutations. However, a considerable proportion of patients suffer from severe immune side effects and fail to respond to ICIs. As effective biomarkers, programmed cell death ligand 1 (PD-L1) expression, microsatellite instability (MSI), the tumor mutation burden (TMB) and tumor-infiltrating lymphocytes (TILs) require invasive procedures that place heavy physical and psychological burdens on patients. This study aims to identify simple and effective markers to optimize patient selection through therapeutic decisions and outcome prediction. Methods: This retrospective study comprised 95 patients with metastatic NSCLC who were treated with ICIs either as the standard of care or in a clinical trial. The following data were extracted from the medical records. The baseline and dynamic neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were calculated in the present study. Responses were assessed by computed tomography (CT) imaging and classified according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 every 6-12 weeks during treatment. Results: In total, 95 patients were included in the present study. The median age of patients was 61 years, 83.2% (79/95) patients were male, 62.1% (59/95) were former or current smokers, 66.3% (63/95) had adenocarcinoma, 93.7% (89/95) had stage IV disease, and 87.4% were without molecular alterations. A higher overall response rate (ORR) and prolonged median progression-free survival (PFS) was observed in patients with a lower cycle 3 (C3) NLR [7.7 vs. 5.5 months, hazard ratio (HR): 1.70, 95% confidence interval (CI): 0.90-3.22; P=0.12] and derived NLR (dNLR) (8.2 vs. 5.6 months, HR: 1.67, 95% CI: 0.94-2.97; P=0.08). After two cycles of ICI treatment, patients who had an increased NLR, dNLR, and PLR had a lower ORR and an inferior median PFS than those with a decreased NLR (5.5 vs. 8.5 months, HR: 1.87, 95% CI: 1.09-3.21; P=0.02), dNLR (5.6 vs. 8.4 months, HR: 1.49, 95% CI: 0.87-2.57; P=0.15), and PLR (11.8 vs. 5.5 months, HR: 2.28, 95% CI: 1.32-3.94; P=0.003). Moreover, patients with both an increased NLR and PLR had a worse ORR and median PFS than those with either an increased NLR or PLR, or both an increased NLR and PLR (11.8 vs. 5.5 vs. 5.6 months, P=0.003). In addition, the dynamic changes in the PLR could serve as an independent predictive factor of PFS in NSCLC patients treated with ICIs. Conclusions: Elevated dynamic changes in the NLR and PLR were associated with lower response rates and shorter PFS in the patients with NSCLC treated with ICIs. Our results also highlight the role of dynamic changes in the PLR in identifying patients with NSCLC who could benefit from ICIs.