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Background: The frequency of primary joint replacement surgery continues to increase worldwide. While largely considered biologically inert entities, an increasing body of evidence continues to validate a not insignificant incidence of allergic reactions to such implants. Little previous work has explored genuinely immune-mediated reactivity in this context. In the absence of a contemporary published summary on the topic, this paper explored the current state of understanding of cobalt/chromium allergy and proposes a patient management algorithm whereby such immune reactions are clinically suggested. Methods: A structured, systematic literature review was performed by following PRISMA search principles to provide an updated review of this area. Results: Thirty-six topic-related articles were identified, the majority reflecting lower tiers of scientific evidence with a lack of homogeneous quantitative data to facilitate valid cohort comparisons. Largely, the available literature represented small case series' or expert opinions. Conclusions: Despite increasing clinical awareness and acknowledgement of true allergy to joint replacement components, this review highlighted that the evidence base underpinning the diagnosis and management of such patients is limited. Both patient-reported metal allergy or skin patch testing are grossly unreliable methods and show almost no correlation with true immune reactivity. Recent studies suggested a potential role for patient-specific in vitro cellular activation testing and/or targeted genetic testing when cobalt/chromium allergy is clinically suspected. However, while likely representing the contemporary "best available" approaches both can be costly undertakings, are not yet universally available, and still require broader validation in non-research settings before wider uptake can be championed. [ABSTRACT FROM AUTHOR]

Transmembrane protease serine 4 (TMPRSS4) is a cancer-associated protease associated with prognosis in various types of cancer. Mechanistically, TMPRSS4 mainly regulates malignant phenotypes, such as tumor invasion and metastasis, by either the epithelial to mesenchymal transition (EMT) program or promoting the proliferation of cancer cells. To date, TMPRSS4 and immune infiltration in thyroid carcinoma (TC) are largely unknown. Thus, this paper evaluated the expression of TMPRSS4 in tumor tissue through the Tumor Immune Estimation Resource (TIMER) database, and Oncomine, and its correlation with clinical parameters by UALCAN databases. Furthermore, we analyzed its prognostic value from Kaplan-Meier Plotter database, and the relationship between TMPRSS4 and the abundance of tumor-infiltrating lymphocytes (TILs) in TC in TISIDB, screening potential immune targets to explore novel mechanisms for the clinical management of TC. Finally, we assessed the correlation between TMPRSS4 and some immune markers to uncover a potential immune-related biomarker in TC patients by TIMER2.0. The results revealed that TMPRSS4 was highly expressed in TC and was also associated with lymphatic metastasis, advanced stage, histological subtype, and favorable clinical outcome. The stratified analysis based on immune cell content showed that decreased TMPRSS4 had worse prognosis in CD8+ T cell-enriched TC patients. TMPRSS4 was positively correlated with tumor immune infiltration and the expression of gene markers of immune cells. Notably, its expression was lower in the lymphocyte-depleted subtype than in other immunosubtypes in TC. Moreover, TMPRSS4 was closely related to chemokines as well as their receptors and the immunosuppressive checkpoints CTLA-4, PD-1, and HLA-G. In conclusion, TMPRSS4 may act as a novel biomarker predicting prognosis and immune infiltration in TC. [ABSTRACT FROM AUTHOR]

Background: Cadonilimab is the first approved dual immune checkpoint inhibitor targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), currently utilized for the treatment of various solid tumors. Oral mucosal adverse reactions, such as oral lichenoid lesions, represent one of the most prevalent immune-related adverse events associated with immune checkpoint antibodies. However, reports detailing oral side effects specifically linked to Cadonilimab are lacking. Documenting these side effects is essential to alert oncologists and stomatologists, facilitating timely intervention for affected patients. Case Presentation: We present a case involving a 35-year-old male patient diagnosed with hepatocellular carcinoma who received Cadonilimab following hepatectomy and subsequently developed extensive oral lichenoid lesions along with mucosal erosion at 13–14 weeks post-treatment initiation. A biopsy was conducted revealing immunohistochemical findings of CD3+, CD4+, CD8+, CD20 + lymphocytes, CD68 + macrophages, and α-SMA + myofibroblasts infiltrating the tissue of the oral lichenoid lesions. The patient's oral lesions improved after administration of systemic and local glucocorticoid therapy alongside cessation of Cadonilimab treatment. Conclusion: This report marks the first documented instance of an oral adverse effect associated with Cadonilimab use. It underscores that administration of this agent may lead to significant lichenoid lesions and erosions within the oral cavity—an issue warranting increased vigilance from both oncologists and stomatologists. [ABSTRACT FROM AUTHOR]

Non-coding RNA expression has shown to have cell type-specificity. The regulatory characteristics of these molecules are impacted by changes in their expression levels. We performed next-generation sequencing and examined small RNA-seq data obtained from 6 different types of blood cells separated by fluorescence-activated cell sorting of severe COVID−19 patients and healthy control donors. In addition to examining the behavior of piRNA in the blood cells of severe SARS-CoV−2 infected patients, our aim was to present a distinct piRNA differential expression portrait for each separate cell type. We observed that depending on the type of cell, different sorted control cells (erythrocytes, monocytes, lymphocytes, eosinophils, basophils, and neutrophils) have altering piRNA expression patterns. After analyzing the expression of piRNAs in each set of sorted cells from patients with severe COVID−19, we observed 3 significantly elevated piRNAs - piR−33,123, piR−34,765, piR−43,768 and 9 downregulated piRNAs in erythrocytes. In lymphocytes, all 19 piRNAs were upregulated. Monocytes were presented with a larger amount of statistically significant piRNA, 5 upregulated (piR−49039 piR−31623, piR−37213, piR−44721, piR−44720) and 35 downregulated. It has been previously shown that piR−31,623 has been associated with respiratory syncytial virus infection, and taking in account the major role of piRNA in transposon silencing, we presume that the differential expression patterns which we observed could be a signal of indirect antiviral activity or a specific antiviral cell state. Additionally, in lymphocytes, all 19 piRNAs were upregulated. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) has a high mortality rate and is one of the most common malignancies in the world. Initially, BC was considered non-immunogenic, but a paradigm shift occurred with the discovery of tumor-infiltrating lymphocytes (TILs) and regulatory T cells (Tregs) in the BC tumor microenvironment. CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) immunotherapy has emerged as a treatment option for BC, but it has limitations, including suboptimal antitumor effects and toxicity. Research has demonstrated that anti-CTLA-4 combination therapies, such as Treg depletion, cancer vaccines, and modulation of the gut microbiome, are significantly more effective than CTLA-4 monoclonal antibody (mAB) monotherapy. Second-generation CTLA-4 antibodies are currently being developed to mitigate immune-related adverse events (irAEs) and augment antitumor efficacy. This review examines anti-CTLA-4 mAB in BC, both as monotherapy and in combination with other treatments, and sheds light on ongoing clinical trials, novel CTLA-4 therapeutic strategies, and potential utility of biomarkers in BC. [ABSTRACT FROM AUTHOR]

Background: Pulmonary embolism (PE) is a life-threatening thromboembolic disease for which there is limited evidence for effective prevention and treatment. Our goal was to determine whether genetically predicted circulating blood cell traits could influence the incidence of PE. Methods: Using single variable Mendelian randomization (SVMR) and multivariate Mendelian randomization (MVMR) analyses, we identified genetic associations between circulating blood cell counts and lymphocyte subsets and PE. GWAS blood cell characterization summary statistics were compiled from the Blood Cell Consortium. The lymphocyte subpopulation counts were extracted from summary GWAS statistics for samples from 3757 individuals that had been analyzed by flow cytometry. GWAS data related to PE were obtained from the FinnGen study. Results: According to the SVMR and reverse MR, increased levels of circulating white blood cells (odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.81-0.95, p = 0.0079), lymphocytes (OR: 0.90, 95% CI: 0.84-0.97, p = 0.0115), and neutrophils (OR: 0.88, 95% CI: 0.81–0.96, p = 0.0108) were causally associated with PE susceptibility. MVMR analysis revealed that lower circulating lymphocyte counts (OR: 0.84, 95% CI: 0.75-0.94, p = 0.0139) were an independent predictor of PE. According to further MR results, this association may be primarily related to HLA-DR+ natural killer (NK) cells. Conclusions: Among European populations, there is a causal association between genetically predicted low circulating lymphocyte counts, particularly low HLA-DR+ NK cells, and an increased risk of PE. This finding supports observational studies that link peripheral blood cells to PE and provides recommendations for predicting and preventing this condition. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with chronic low-grade inflammation, which is linked to cancer development. Abdominal obesity (a body mass index, ABSI), however, has unusually been associated inversely with cutaneous malignant melanoma (CMM), while general obesity (body mass index, BMI) is associated positively. Leucocytes participate in inflammation and are higher in obesity, but prospective associations of leucocytes with cutaneous malignant melanoma are unclear. Methods: We examined the prospective associations of neutrophil, lymphocyte, and monocyte counts (each individually), as well as the prospective associations of ABSI and BMI, with cutaneous malignant melanoma in UK Biobank. We used multivariable Cox proportional hazards models and explored heterogeneity according to sex, menopausal status, age (≥ 50 years at recruitment), smoking status, ABSI (dichotomised at the median: ≥73.5 women; ≥79.8 men), BMI (normal weight, overweight, obese), and time to diagnosis. Results: During a mean follow-up of 10.2 years, 2174 CMM cases were ascertained in 398,450 participants. There was little evidence for associations with neutrophil or lymphocyte counts. Monocyte count, however, was associated inversely in participants overall (HR = 0.928; 95%CI: 0.888–0.971; per one standard deviation increase; SD = 0.144*109/L women; SD = 0.169*109/L men), specifically in older participants (HR = 0.906; 95%CI: 0.862–0.951), and more clearly in participants with low ABSI (HR = 0.880; 95%CI: 0.824–0.939), or with BMI ≥ 25 kg/m2 (HR = 0.895; 95%CI: 0.837–0.958 for overweight; HR = 0.923; 95%CI: 0.848–1.005 for obese). ABSI was associated inversely in pre-menopausal women (HR = 0.810; 95%CI: 0.702–0.935; SD = 4.95) and men (HR = 0.925; 95%CI: 0.867–0.986; SD = 4.11). BMI was associated positively in men (HR = 1.148; 95%CI: 1.078–1.222; SD = 4.04 kg/m2). There was little evidence for heterogeneity according to smoking status. The associations with monocyte count and BMI were retained to at least 8 years prior to diagnosis, but the association with ABSI was observed up to 4 years prior to diagnosis and not for longer follow-up time. Conclusions: Monocyte count is associated prospectively inversely with the risk of developing CMM in older individuals, while BMI is associated positively in men, suggesting a mechanistic involvement of factors related to monocytes and subcutaneous adipose tissue in melanoma development. An inverse association with ABSI closer to diagnosis may reflect reverse causality or glucocorticoid resistance. [ABSTRACT FROM AUTHOR]

Background: Patients with immunocompromise were suspected to encounter a high risk for severe coronavirus disease 2019 (COVID-19) infection on early period; however, data is lacking nowadays and immune response remain unclear. Methods: In this retrospective study, internet questionnaire survey and medical records were acquired in pediatric hematology oncology patients. Clinical severity, immunological characteristics, and outcomes were analyzed from December 1, 2022 to January 31, 2023 at the 3rd year of pandemic in China. Results: A total of 306 patients were included, with 21 patients (6.9%) asymptomatic, 262 (85.6%) mild severity, 17 (5.6%) moderate severity, 5 (1.6%) severe severity, and 1 (0.3%) critical severity. Seventy-eight (25.5%) patients were on intensive chemotherapy, and 32.0% children were on maintenance chemotherapy. Delays in cancer therapy occurred in 86.7% patients. Univariable analysis revealed active chemotherapy (P < 0.0001), long duration of symptom (P < 0.0001), low lymphocytes count (P = 0.095), low CD3 + and CD8 + T cell count (P = 0.013, P = 0.022), high percentage of CD4 + TCM (P = 0.016), and low percentage of transitional B cells (P = 0.045) were high risk factors for severe COVID-19 infection. Cox regression model showed that the absolute lymphocytes count (P = 0.027) and long duration of symptom (P = 0.002) were the independent factors for severity. Patients with CD8 + dominant and B cell depletion subtype wasn't related with severity, but had higher percentage of CD8 + effector memory T cells (TEM) and terminally differentiated effector memory T cells (TEMRA) (P < 0.001, P < 0.001), and a longer COVID-19 duration (P = 0.045). Conclusion: The severity was relatively mild in children with immunodeficiencies in the third year of COVID-19 pandemic. Low lymphocyte count and long duration of symptom were the independent risk factors with COVID-19 severity. Delays in cancer care remain a major concern and the long outcome is pending. [ABSTRACT FROM AUTHOR]

Background and purpose: The systemic immune-inflammation index (SII), a novel inflammation index derived from the counts of circulating platelets, neutrophils and lymphocytes, has been studied in the treatment of acute cancer and ischemic stroke (AIS). However, the clinical value of the SII in postoperative delirium patients has not been further investigated. The purpose of our research was to study the incidence and preoperative risk factors for postoperative delirium (POD) and verify whether the SII could serve as a potential marker for POD in older intertrochanteric fracture patients. Finally, we created a novel nomogram for predicting POD in older patients with intertrochanteric fractures. Methods: We enrolled elderly patients with intertrochanteric fractures who underwent proximal femoral nail antirotation (PFNA) between February 2021 and April 2023. Univariate and multivariate logistic analyses were subsequently performed to confirm the risk factors and construct a nomogram model.Calibration curve and clinical decision curve analysis (DCA) were used to assess the model's fitting performance. The performance of the nomogram was evaluated for discrimination, calibration, and clinical utility. Results: A total of 293 patients were eligible for inclusion in the study, 25.6% (75/293) of whom had POD. The POD patients had higher SII values than the non-POD patients. The SII was strongly correlated with POD in older intertrochanteric fracture patients, and the optimal cutoff value was 752.6 × 109. Multivariate analysis revealed that age, diabetes, total albumin, SII > 752.6 × 109 and a CRP > 20.25 mg/L were independent risk factors for POD patients. By incorporating these 5 factors, the model achieved a concordance index of 0.745 (95% CI, 0.683–0.808) and had a well-fitted calibration curve and good clinical application value. Conclusion: The SII is a simple and valuable biomarker for POD, and the new nomogram model can be used to accurately predict the occurrence of POD. They can be utilized in clinical practice to identify those at high risk of POD in older intertrochanteric fracture patients. [ABSTRACT FROM AUTHOR]

Background: Methanolic and chloroformic extract of Achillea millefolium and Chaerophyllum villosum were evaluated for HPLC analysis, genotoxic and antioxidant potential. Materials and methods: Genotoxic activity was carried out on human blood lymphocytes via comet assay and antioxidant activity was studied through DPPH method. Results: The genotoxic potential of A. millefolium and C. villosum's methanolic and chloroformic extract was analysed using comet assay technique. Comet shaped human lymphocytes cells were observed when treated with different concentrations (50 mg/mL, 75 mg/mL, 100 mg/mL) of methanolic and chloroformic extract of both plants. Reading was taken on the basis of damaged DNA head and tail length. Greater the length of tail as compared to head, greater will be the damage and vice versa. Total comet score was obtained from A. millefolium subjected to different concentrations. After a time interval of 24 h both the extract showed dose dependant genoprotection with maximum genoprotectivity at 98.7 ± 12.7 and 116 ± 5.3 at 50 mg/100 mL for methanolic and chloroformic extract respectively. Similarly Total Comet score was obtained from C. villosum subjected to different concentrations of methanolic and chloroformic extract. After 24 h exhibited dose dependent genoprotection with maximum protectivity at 85.7 ± 22.0 and 101.7 ± 8.6 at 50 mg/100 mL for methanolic and chloroformic extract were determined. The antioxidant activity revealed that methanolic extract of A. millefolium showed highest antioxidant activity (84.21%) at 300 mg/ml after 90 min while the chloroformic extract of C. villosum exhibited highest (68.46%) antioxidant activity (59.69%) at 300 µg/ml after 90 min but less than the standard drug ascorbic acid (88.72%). Quantitative phytochemical screening revealed high percentage of alkaloids (27.4%), Phenols (34.5%), Flavonoids (32.4%) as compared to Tannins (12%) in methanolic extract of A.millefolium. While high percentage of alkaloids (31.4), Phenols (19.3%), Flavonoids (35.5%) as compared to Tannins (16.6%) in chloroformic extract of C. villosum. Conclusion: The present results showed that A. millefolium and C. villosum possess a number of important compounds and revealed genoprotective property which may be used to treat several genetic disorders such as alzeimer's disease in future (Grodzicki W, Dziendzikowska K, Antioxidants 9(3):229, 2020). [ABSTRACT FROM AUTHOR]

Background: Bronchopulmonary Dysplasia (BPD) in infants born prematurely is a risk factor for chronic airway obstruction later in life. The distribution of T cell subtypes in the large airways is largely unknown. Objective: To characterize cellular and T cell profiles in the large airways of young adults with a history of BPD. Methods: Forty-three young adults born prematurely (preterm (n = 20), BPD (n = 23)) and 45 full-term-born (asthma (n = 23), healthy (n = 22)) underwent lung function measurements, and bronchoscopy with large airway bronchial wash (BW). T-cells subsets in BW were analyzed by immunocytochemistry. Results: The proportions of both lymphocytes and CD8 + T cells in BW were significantly higher in BPD (median, 6.6%, and 78.0%) when compared with asthma (3.4% and 67.8%, p = 0.002 and p = 0.040) and healthy (3.8% and 40%, p < 0.001 and p < 0.001). In all adults born prematurely (preterm and BPD), lymphocyte proportion correlated negatively with forced vital capacity (r= -0.324, p = 0.036) and CD8 + T cells correlated with forced expiratory volume in one second, FEV1 (r=-0.448, p = 0.048). Correlation-based network analysis revealed that lung function cluster and BPD-birth cluster were associated with lymphocytes and/or CD4 + and CD8 + T cells. Multivariate regression analysis showed that lymphocyte proportions and BPD severity qualified as independent factors associated with FEV1. Conclusions: The increased cytotoxic T cells in the large airways in young adults with former BPD, suggest a similar T-cell subset pattern as in the small airways, resembling features of COPD. Our findings strengthen the hypothesis that mechanisms involving adaptive and innate immune responses are involved in the development of airway disease due to preterm birth. What is already known on this topic: Bronchopulmonary Dysplasia (BPD) in infants born prematurely is a risk factor for chronic airway obstruction in adulthood. Cytotoxic T cells are increased in bronchoalveolar lavage in adults with former BPD. What this study adds: We are able to demonstrate that inflammatory cell profiles in the bronchial wash from the large airway of preterm adults differ from healthy subjects born at term. Subjects with a history of BPD display an increased proportion of lymphocytes, mainly CD8 + T cells, and a lower proportion of CD4 + T cells. Furthermore, the number of cytotoxic T cells is associated with lung function. How this study might affect research practice and/or policy: This study provides evidence of an immunological profile characterized by increased cytotoxic T cells in adults born prematurely, which suggests the involvement of both adaptive and innate immune mechanisms in the development of airway disease associated with preterm birth. [ABSTRACT FROM AUTHOR]

Background: This study aims to assess the effectiveness of neutrophil/lymphocyte ratio (NLR) and C-reactive protein (CRP) in diagnosing cholecystolithiasis with cholecystitis in elderly patients. Additionally, the study seeks to determine the predictive value of preoperative NLR in determining the severity of the condition in this population. Methods: This study is a retrospective cohort study, including 160 elderly patients with cholecystolithiasis with cholecystitis (45 cases of simple cholecystitis, 58 cases of suppurative cholecystitis, 57 cases of gangrenous cholecystitis) and 60 cases of normal gallbladder histology. The study collected clinical data of the patients detected the preoperative CRP content, neutrophil, and lymphocyte levels through blood routine tests, and calculated the NLR value. The diagnostic value of NLR and CRP was determined by using the Receiver Operating Characteristic Curve (ROC), and the optimal value of preoperative NLR related to the severity of elderly patients with cholecystolithiasis with cholecystitis was identified. Results: This study found that for elderly patients with cholecystolithiasis with cholecystitis, preoperative NLR and CRP levels can be used to distinguish the condition. The critical value for NLR was found to be 2.995 (95% CI, 0.9465–0.9853; P < 0.001) with an area under the ROC curve of 0.9659, while the critical value for CRP was 13.05 (95% CI, 0.9284–0.9830; P < 0.001) with an area under the ROC curve of 0.9557. Both NLR and CRP were found to have equivalent diagnostic abilities. Additionally, the study found that there were significant differences in neutrophil and lymphocyte levels in elderly patients with different severity levels, with NLR increasing as severity increased (P < 0.001). The study identified cut-off values for preoperative NLR that could distinguish Simple cholecystitis and Purulent cholecystitis, as well as Purulent cholecystitis and Gangrenous cholecystitis in elderly patients with cholecystolithiasis, with respective AUCs of 0.8441 (95% CI: 0.7642–0.9239; P < 0.001) and 0.7886(95% CI: 0.7050–0.8721, P < 0.001), sensitivities of 91.38% and 87.72%, and specificities of 73.33% and 63.79%. Conclusions: Preoperative NLR and CRP values can serve as indicators to detect cholecystolithiasis with cholecystitis in elderly patients. Additionally, NLR has been recognized as a potential tool to differentiate the severity of cholecystolithiasis with cholecystitis in the elderly population. [ABSTRACT FROM AUTHOR]

Introduction: In vitro or in vivo depletion of alloreactive T cells can facilitate haplo-identical hematopoietic stem cell transplantation (HSCT). Very satisfactory transplant outcomes were thus reported for TCRαβ/CD19-depleted hematopoietic stem/progenitor cell (HSPC) grafts. The current semi-automatic manufacturing process on the CliniMACS Plus, although robust, still requires a significant amount of manual labor to be completed. Towards advancing and further facilitating large scale cell processing, a new TCRαβ/CD19 depletion module combined with the previously described CD45RA depletion module (to serve as allo-reactivity attenuated donor lymphocyte infusion) was established on the CliniMACS Prodigy. Methods: We evaluated six apheresis products from G-CSF-mobilized volunteer donors which were split automatically by the Prodigy, one portion each depleted of CD45RA+ or of TCRαβ+ and CD19+ cells. We investigated critical quality attributes for both products. Products were assessed for recovery of HSPCs and mature subsets, as well as depletion efficiency of targeted cells using flow cytometry. Effects of apheresis and product age post 48 h storage at 2–6 °C as well as freeze-thawing on product viability and recovery of WBC and HPSCs were assessed by flow cytometry. Results: Ten sequential automatic processes were completed with minimal hands-on time beyond tubing set installation. Depletion efficiency of CD45RA+ resp. TCRαβ+ and CD19+ cells was equivalent to previous reports, achieving mean depletions of 4 log of targeted cells for both products. HSPC products retained TCRγδ+ and NK cells. 48 h storage of apheresis product was associated with the expected modest loss of HSPCs, but depletions remained efficient. Depleted products were stable until at least 72 h after apheresis with stem cell viabilities > 90%. Freeze-thawing resulted in loss of NK cells; post-thaw recovery of viable CD45+ and HSPCs was > 70% and in line with expectation. Conclusion: The closed, GMP-compatible process generates two separate medicinal products from the same mobilized apheresis product. The CD45RA-depleted products contained functional memory T cells, whereas the TCRαβ/CD19-depleted products included HSPCs, TCRγδ+ and NK cells. Both products are predicted to be effectively depleted of GVH-reactivity while providing immunological surveillance, in support of haplo-identical HSCT. [ABSTRACT FROM AUTHOR]

Background: The migration of lymphocytes shares many similarities in mode and mechanism with the metastasis of lung cancer tumor cells. But changes in the expression of lymphocyte migration regulation related proteins in urine exosomes remain unclear. This study is to investigate the expression changes of lymphocyte migration regulation related proteins in urine exosomes of lung cancer patients, and further verify their correlation with the development and progression of lung cancer. Methods: Urine exosomes were collected from lung cancer patients and healthy people aged 15–79 years. Mass spectrometry was used to screen and explore the expression changes of lymphocyte migration regulation related proteins in healthy people of different ages. Enzyme-linked immunosorbent assay and western blotting were used to detect the expression changes of lymphocyte migration regulation related proteins in lung cancer patients. Results: Analyzing the data of urine exosome proteomics, a total of 12 lymphocyte related proteins were identified, 5 of which were lymphocyte migration regulation related proteins. Among these proteins, WASL and STK10 proteins showed a gradual decrease in expression with age, and WNK1 protein showed a gradual increase. Lung cancer patients had reduced expression of WASL and increased expression of STK10 and WNK1 proteins in urine exosomes compared to normal people. Urine exosome WASL, STK10, and WNK1 were diagnosed with lung cancer, with a combined AUC of 0.760. Conclusions: Lymphocyte migration regulation related proteins were differentially expressed in the urine exosome of lung cancer patients, and WASL, STK10 and WNK1 may serve as potential biomarkers for lung cancer diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: Deep vein thrombosis (DVT) has been considered as a frequent and serious consequence of intertrochanteric femoral fractures in the elderly. Several negative repercussions of DVT can be considerably mitigated by its timely recognition and treatment. The current work was aimed at exploring the factors independently predicting DVT among cases suffering from intertrochanteric femoral fractures and validate their predictive usefulness in diagnosing DVT. Methods: Between April 2017 and July 2022, clinical information from 209 cases showing preoperative DVT for femoral intertrochanteric fractures were retrospectively evaluated. In patients with femoral intertrochanteric fractures, logistic regression analysis with a backward stepwise method was adopted for detecting independent predictors for the diagnosis of preoperative DVT. Using multivariate logistic regression, a nomogram prediction model was developed and verified with the testing group. Results: According to multivariate logistic regression model, body mass index (BMI) (OR 0.79, 95% CI 0.63–0.99, P = 0.042), neutrophil/lymphocyte ratio (NLR) (OR 7.29, 95% CI 1.53, 34.64, P = 0.0012), and systemic immune-inflammation index (SII) (OR 6.61, 95% CI 2.35, 18.59, P = 0.001) were independent predictors for DVT before surgery among cases developing intertrochanteric femoral fracture. AUC values were 0.862 and 0.767 for training and testing groups, separately, while their mean errors in the calibration curve were 0.027 and 0.038 separately. Decision curve analysis (DCA) curve revealed a high value of clinical application for both groups. Conclusion: Upon admission, BMI, NLR, and SII are independent predictors of DVT before surgery among cases developing intertrochanteric femoral fractures. Additionally, the nomogram based on the BMI, NLR, and SII can assist clinicians in determining if preventive and symptomatic therapies are required to improve DVT prognosis and reduce its associated mortality. [ABSTRACT FROM AUTHOR]

With a significant rise in the number of arthroplasty procedures performed worldwide, the increasing revision burden posed by periprosthetic joint infection (PJI) is a matter of growing concern. In spite of various attempts to diagnose PJI, there are no defined tests that can be called a gold standard. Given the importance of early diagnosis in PJI, newer tests and biomarkers have been introduced to improve cumulative diagnostic accuracy. Novel biomarkers like calprotectin, lipocalcin, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and platelet-to-mean platelet volume ratio have demonstrated a potential as diagnostic biomarkers for PJI. This article discusses the relevance of available and newly described diagnostic biomarkers to provide a perspective on the practical applicability in current medical practice, as well as highlights some recent advances in biomarkers for the diagnosis of PJI. [ABSTRACT FROM AUTHOR]

Background: Although immune cells are involved in acute coronary syndrome (ACS), few studies have explored the association of incident ACS with the relative immune cell proportions. We aimed to investigate the association of immune cell proportions with the incidence and risk factors of ACS in the Dongfeng–Tongji cohort. Methods: We conducted the analyses with 38,295 subjects from the first follow-up of the Dongfeng–Tongji cohort, including DNA methylation profiles for 1570 individuals. The proportions of immune cell types were observed from routine blood tests or estimated from DNA methylation profiles. For both observed and estimated immune cell proportions, we tested their associations with risk factors of ACS by multivariable linear regression models. In addition, the association of each immune cell proportion with incident ACS was assessed by the Cox regression model and conditional logistic regression model, respectively, adjusting for the risk factors of ACS. Findings: The proportions of lymphocytes, monocytes, and neutrophils showed strong associations with sex, followed by diabetes. Moreover, sex and current smoking were the two factors with strongest association with the proportions of lymphocyte subtypes. The hazard ratio (HR) and 95% confidence interval (CI) of incident ACS per standard deviation (SD) increase in proportions of lymphocytes and neutrophils were 0.91 (0.85–0.96) and 1.10 (1.03–1.16), respectively. Furthermore, the OR (95% CI) of incident ACS per SD increase in proportions of NK cells, CD4+ T cells, and B cells were 0.88 (0.78–0.99), 1.15 (1.03–1.30), and 1.13 (1.00–1.26), respectively. Interpretation: The proportions of immune cells were associated with several risk factors of ACS, including sex, diabetes, and current smoking. In addition, proportion of neutrophils had a risk effect, while proportion of lymphocytes had a protective effect on the incidence of ACS. The protective effect of lymphocytes was probably driven by NK cells. [ABSTRACT FROM AUTHOR]

Background: Hip fractures are common in elderly patients, and almost all the patients undergo surgery. This study aimed to develop a novel modified lymphocyte C-reactive protein (CRP) score (mLCS) to simply and conveniently predict 3-year mortality in elderly patients undergoing intertrochanteric fracture surgery. Methods: A retrospective study was conducted on elderly patients who underwent intertrochanteric fracture surgery between January 2014 and December 2017. The mLCS was developed according to the value of CRP and lymphocyte counts. Univariate and multivariate Cox regression analyses were used to identify independent risk factors for 3-year mortality after surgery. The performances of the lymphocyte CRP score (LCS) and mLCS to predict 3-year mortality were then compared using C-statistics, decision curve analysis (DCA), net reclassification index (NRI) and integrated discrimination improvement (IDI). Results: A total of 291 patients were enrolled, of whom 52 (17.9%) died within 3 years after surgery. In the multivariate Cox regression analysis, mLCS (hazard ratio (HR), 5.415; 95% confidence interval (CI), 1.743–16.822; P = 0.003) was significantly associated with postoperative 3-year mortality. The C-statistics of LCS and mLCS for predicting 3-year mortality were 0.644 and 0.686, respectively. The NRI (mLCS vs. LCS, 0.018) and IDI (mLCS vs. LCS, 0.017) indicated that the mLCS performed better than the LCS. DCA also showed that mLCS had a higher clinical net benefit. Conclusions: mLCS is a promising predictor that can simply and conveniently predict 3-year mortality in elderly patients undergoing intertrochanteric fracture surgery. [ABSTRACT FROM AUTHOR]

Background: The neutrophil-to-lymphocyte ratio (NLR) is positively associated with unfavorable outcomes in patients with cerebral infarction. This study aimed to investigate the relationship between the NLR and the short-term clinical outcome of acute pontine infarction.Methods: Patients with acute pontine infarction were consecutively included. Clinical and laboratory data were collected. All patients were followed up at 3 months using modified Rankin Scale (mRS) scores. An unfavorable outcome was defined as an mRS score ≥ 3. Receiver operating characteristic (ROC) curve analysis was used to calculate the optimal cutoff values for patients with acute pontine infarction. risk factors can be predictive factors for an unfavorable outcome after acute pontine infarction.Results: Two hundred fifty-six patients with acute pontine infarction were included in this study. The NLR was significantly higher in the unfavorable outcome group than in the favorable outcome group (P < 0.05). Additionally, the infarct size was significantly higher in the high NLR tertile group than in the low NLR tertile group (P < 0.05). Multivariate logistic regression analysis revealed that the baseline National Institutes of Health Stroke Scale (NIHSS) score, NLR, platelet count, and fasting blood glucose (FBG) level were significantly associated with unfavorable outcomes 3 months after acute pontine infarction. The optimal cutoff value of the NLR for predicting the 3-month outcome of acute pontine infarction was 3.055. The negative and positive predictive values of NLR were 85.7% and 61.3%, respectively, and the sensitivity and specificity of NLR were 69.2% and 80.9%.Conclusions: We found that the NLR may be an independent predictive factor for the outcome of acute pontine infarction. [ABSTRACT FROM AUTHOR]

Background: It is difficult to distinguish the clinical and histopathological aspects of oral lichen planus lesions from those of oral lichenoid reaction. Some criteria were proposed to distinguish them, mainly because they have different biological behaviors. The aim of the present study was to compare the lymphocyte population and the expression of E-selectin between these lesions. Methods: Participants with a clinical diagnosis of oral lichen planus (GOLP) and oral lichenoid reaction (GOLR) who needed to perform a biopsy were selected. The tissue was frozen and immunostaining was performed for CD3/CD4, CD3/CD8, CD4/CLA, CD8/CLA, and CD62E. The analysis of each immunostaining was accomplished using the ImageJ program. Results: In total, 25 participants with oral lichen planus and 11 with oral lichenoid reaction were seen. In the evaluation of CD3 + CD4+/CD3 + and CD3 + CD8+/CD3 + proportions, there was a higher percentage of these cells in the oral lichen planus group when compared with the oral lichenoid reaction group (p = 0.027 and p = 0.038 respectively). The average number of CLA + lymphocytes for CD4+/CLA + and CD8+/CLA + in both groups was not statistically significant (p = 0.840; d = 0.363). In GOLP, the number of CD4 + CLA+/E-selectin and CD8 + CLA+/E-selectin was not statistically significant (p = 0.951 and p = 0.454 respectively); neither in GOLR (p = 0.454 and p = 0.989 respectively). Conclusion: Our results indicate that CD3 + CD4+, CD3 + CD8+, CD4 + CLA+, CD8 + CLA + lymphocytes and E-selectin are present in both lesions. However, the proportion of CD3 + CD4+/CD3 + and CD3 + CD8/CD3 + cells is higher in the oral lichen planus group when compared with the oral lichenoid reaction group, suggesting that these cells may be important for the etiopathogenic mechanism of these lesions. [ABSTRACT FROM AUTHOR]

Background: Systemic inflammation is currently regarded as a hallmark of cancer. This study aimed to accurately clarify the prognostic value of various inflammatory markers in patients with stage IV cancer.Methods: This study assessed 2,424 patients with cancer diagnosed with cancer in tumor, node, metastasis (TNM) stage IV. After evaluating the predictive value of 13 inflammatory indicators for patient prognosis using the C index, the lymphocyte C-reactive protein ratio (LCR) was selected to elucidate the prognostic and predictive values in patients with stage IV cancer. Kaplan-Meier and Cox proportional hazards regression models were used to analyze long-term survival.Results: A total of 1,457 men (60.1%) and 967 women (39.9%) diagnosed with TNM stage IV cancer were enrolled. A ratio of 2,814 was defined as the optimal cut-off value for the LCR. The LCR was the most accurate prognosis predictor for patients with stage IV cancer among the 13 inflammatory nutritional markers evaluated. The multivariate-adjusted restricted cubic spline plot suggested that LCR had an L-shaped dose-response association with all-cause mortality risk. Patients with lower LCR levels tended to present with worse prognoses. Kaplan-Meier curves and log-rank test results showed that the high LCR groups (LCR ≥ 2,814) exhibited a better prognosis, whereas patients with stage IV cancer of different sex and tumor types (for example, gastrointestinal tumor, non-gastrointestinal tumor, and lung cancer) had a worse survival time.Conclusion: The LCR score can be regarded as a stable and useful biomarker to predict prognosis in patients with TNM stage IV compared to other evaluated inflammation indicators. [ABSTRACT FROM AUTHOR]

Background: Immune system dysregulation plays a vital role in the pathogenesis of neurodegenerative diseases, even considered to be as important as classical pathological protein aggregation assumption. However, the associations of immune-mediated diseases with incident dementia are unclear and need to be clarified in prospective studies with a large population and long follow-up time. Methods: We investigated the relationship between any or individual immune-mediated diseases and incident dementia based on a prospective cohort UK Biobank. The risk for dementia was assessed with multivariable hazard ratio (HR) and 95% confidence interval (CI) after adjusting for various potential confounders using time-varying Cox proportional hazards regression. We also performed the subgroup Cox analysis stratified by time since immune-mediated diseases and gender. Causal mediation analyses with 1000 bootstrapped iterations were conducted to explore the mediation effects of peripheral immune cells on the associations of immune-mediated diseases with dementia. Results: A total of 375,894 participants were included in the study, among which 5291 developed dementia during a median follow-up of 9.08 years. Immune-mediated diseases were associated with an increased risk of dementia (HR, 1.10; 95% CI, 1.00–1.21), and the risk was highest between 1 and 2 years after immune-mediated diseases onset (HR, 2.74; 95% CI, 1.86–4.04). Females who suffered from immune-mediated diseases were more prone to AD, while males were more susceptible to VD. Four of the individual immune-mediated diseases including type I diabetes mellitus (HR, 2.49; 95% CI, 1.97–3.15), rheumatic fever or rheumatic heart diseases (HR, 1.36; 95% CI, 1.05–1.77), multiple sclerosis (HR, 2.87; 95% CI, 1.92–4.30), and necrotizing vasculopathies (HR, 1.71; 95%CI, 1.03–2.85) were significantly related to higher dementia incidence. The relationship between immune-mediated diseases and dementia was partially mediated by peripheral immune cells including neutrophils and lymphocytes. Conclusions: In this large cohort study, immune-mediated diseases were proven to be significantly associated with an increased risk of incident dementia, especially for type I diabetes mellitus which was observed to be related to the higher incidence of all types of dementia. Our findings could provide new sights on dementia pathogenesis and intervention from the perspective of systemic immunology and immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Background: As an original traditional Chinese medicinal formula, Qin Huang formula (QHF) is used as adjuvant therapy for treating lymphoma in our hospital and has proven efficacy when combined with chemotherapy. However, the underlying mechanisms of QHF have not been elucidated. Methods: A network pharmacological-based analysis method was used to screen the active components and predict the potential mechanisms of QHF in treating B cell lymphoma. Then, a murine model was built to verify the antitumor effect of QHF combined with Adriamycin (ADM) in vivo. Finally, IHC, ELISA, 18F-FDG PET-CT scan, and western blot were processed to reveal the intriguing mechanism of QHF in treating B cell lymphoma. Results: The systemic pharmacological study revealed that QHF took effect following a multiple-target and multiple-pathway pattern in the human body. In vivo study showed that combination therapy with QHF and ADM potently inhibited the growth of B cell lymphoma in a syngeneic murine model, and significantly increased the proportion of tumor infiltrating CD4+ and CD8+ T cells in the tumor microenvironment (TME). Furthermore, the level of CXCL10 and IL-6 was significantly increased in the combination group. Finally, the western blot exhibited that the level of TLR2 and p38 MAPK increased in the combination therapy group. Conclusion: QHF in combination of ADM enhances the antitumor effect of ADM via modulating tumor immune microenvironment and can be a combination therapeutic strategy for B cell lymphoma patients. [ABSTRACT FROM AUTHOR]

Background: Melatonin, an indoleamine produced by the pineal gland, plays a pivotal role in maintaining circadian rhythm homeostasis. Recently, the strong antioxidant and anti-inflammatory properties of melatonin have attracted attention of researchers. We evaluated the therapeutic efficacy of melatonin in experimental autoimmune uveitis (EAU), which is a representative animal model of human autoimmune uveitis.Methods: EAU was induced in mice via immunization with the peptide interphotoreceptor retinoid binding protein 1-20 (IRBP1-20). Melatonin was then administered via intraperitoneal injection to induce protection against EAU. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the disease progression. T lymphocytes accumulation and the expression of inflammatory cytokines in the retinas were assessed via flow cytometry and RT-PCR, respectively. T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cells were detected via flow cytometry for both in vivo and in vitro experiments. Reactive-oxygen species (ROS) from CD4 + T cells was tested via flow cytometry. The expression of thioredoxin-interacting protein (TXNIP) and hypoxia-inducible factor 1 alpha (HIF-1α) proteins were quantified via western blot.Results: Melatonin treatment resulted in notable attenuation of ocular inflammation in EAU mice, evidenced by decreasing optic disc edema, few signs of retinal vasculitis, and minimal retinal and choroidal infiltrates. Mechanistic studies revealed that melatonin restricted the proliferation of peripheral Th1 and Th17 cells by suppressing their transcription factors and potentiated Treg cells. In vitro studies corroborated that melatonin restrained the polarization of retina-specific T cells towards Th17 and Th1 cells in addition to enhancing the proportion of Treg cells. Pretreatment of retina-specific T cells with melatonin failed to induce EAU in naïve recipients. Furthermore, the ROS/ TXNIP/ HIF-1α pathway was shown to mediate the therapeutic effect of melatonin in EAU.Conclusions: Melatonin regulates autoimmune T cells by restraining effector T cells and facilitating Treg generation, indicating that melatonin could be a hopeful treatment alternative for autoimmune uveitis. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes. DR involves a state of systemic inflammation, and chronic inflammation can promote microvascular and macrovascular diseases in diabetic patients and accelerate disease progression. Ultrawide-field FFA (UWFA) systems are increasingly being used to examine a wider retina. The aim of this study was to explore the correlation between the different manifestations of retinopathy under UWFA and the systemic indicators of white blood cells in patients with diabetic retinopathy.Methods: This retrospective study included the hospitalized DR patients in the Department of Ophthalmology and Endocrinology of the Affiliated Hospital 2 of Nantong University between January 2016 and March 2019. This study examined the correlations between the UWFA examination results and glycated hemoglobin (HbA1c), routine blood tests,and the neutrophil-to-lymphocyte ratio of patients with clinically diagnosed DR during hospitalization.Results: A total of 115 patients with DR (53 females and 62 males) were included (199 eyes: 102 right eyes and 97 left eyes). UWFA revealed that most eyes (77.4%) had grade 4 microvascular leakage, 52.8% had grade 0 capillary non-perfusion area, 59.3% had grade 0 neovascularization, and 92.0% had grade 0 fibrous proliferative membranes. Microvascular leakage was correlated with the NLR (r = 0.186, P = 0.027). Capillary non-perfusion area was correlated with the monocyte ratio (r = 0.144, P = 0.042) and the eosinophil ratio (r = 0.123, P = 0.044). Neovascularization was correlated to the monocyte ratio (r = 0.324, P = 0.018). Finally, the fibrous proliferative membrane was correlated to the monocyte ratio (r = 0.418, P = 0.002). Only the eosinophil ratio was independently associated with proliferative DR (odds ratio = 1.25, 95% confidence interval: 1.04-1.51, P = 0.018).Conclusion: The results of UWFA imaging in patients with DR are correlated with white blood cell population indexes. The eosinophil ratio was independently associated with proliferative DR. [ABSTRACT FROM AUTHOR]

Background: Ropivacaine oil delivery depot (RODD) can be used to treat postoperative incision pain. The aim was to study pharmacodynamics, toxicity and toxicokinetics of RODD. Methods: The base research of RODD were conducted. Thirty rabbits were randomly divided into saline, solvent, ropivacaine aqueous injection (RAI) 0.9 mg, RODD 0.9 mg and RODD 3 mg groups. The sciatic nerve of rabbits were isolated, dripped with RODD and the effect of nerve block were observed. In toxicity study, the rats were divided into saline, solvent and RODD 75, 150 and 300 mg/kg groups, 30 rats per group. In toxicokinetics, rats were divided into RODD 75, 150 and 300 mg/kg groups, 18 rats per group. The rats were subcutaneously injected drugs. Results: The analgesic duration of RODD 3 mg and RAI 0.9 mg blocking ischiadic nerve lasted about 20 h and 2 h, respectively, and their blocking intensity was similar. The rats in RODD 75 mg/kg did not show any toxicity. Compared with saline group, in RODD 150 mg/kg group neutrophils and mononuclear cells increased, lymphocytes decreased and albumin decreased(P < 0.05), and pathological examination showed some abnormals. In RODD 300 mg/kg group, 10 rats died and showed some abnormalities in central nerve system, hematologic indexes, part of biochemical indexes, and the weights of spleen, liver, and thymus. However, these abnormal was largely recovered on 14 days after the dosing. The results of toxicokinetics of RODD 75 mg/kg group showed that the Cmax was 1.24 ± 0.59 µg/mL and the AUC(0-24 h) was 11.65 ± 1.58 h·µg/mL. Conclusions: Subcutaneous injection RODD releases ropivacaine slowly, and shows a stable and longer analgesic effect with a large safety range. [ABSTRACT FROM AUTHOR]

Background: The most critical concern for the management of childhood intussusception is bowel resection due to intestinal ischemia and necrosis. The early prediction of this problem is of great importance. We investigated the value of various combinations of inflammatory factors to predict intestinal necrosis and resection.Methods: We retrospectively reviewed the medical records of pediatric patients with intussusception who underwent surgical management. During the research period, 47 patients who underwent intestinal resection due to intestinal necrosis and 68 patients who did not undergo intestinal resection were enrolled. We evaluated the diagnostic value of various combinations of inflammatory markers from preoperative laboratory analyses using the receiver operating characteristic (ROC) method.Results: In the current cohort, 115 patients underwent operations for intussusception; among them, 47 patients (40.9%) underwent intestinal resections. In the patients with intestinal resection, the neutrophil count(p = 0.013), CRP level(p = 0.002), platelet-lymphocyte ratio (PLR, p = 0.008), NLR (neutrophil-lymphocyte ratio, p = 0.026), and LCR (lymphocyte-CRP ratio, p < 0.001) values were significantly higher than those in the patients without any resection. The receiver operating characteristic (ROC) analysis results showed that the combination of lymphocytic count along with C-reactive protein levels (LCR) demonstrated the highest correlation with intestinal resection due to intussusception compared with other parameters in the patients, with a sensitivity of 0.82 (0.73-0.86) and specificity of 0.80 (0.57-0.94) for the diagnosis of strangulation.Conclusion: The preoperative LCR level is a useful marker to predict the need for intestinal resection due to intestinal necrosis in patients with intussusception. [ABSTRACT FROM AUTHOR]