Eosinophil to lymphocyte ratio may predict OCS reduction and change in quality of life (AQLQ) resulting from asthma biological treatment.

OBJECTIVES: Simple clinical parameters that could be helpful in choice of monoclonal antibodies and prediction of their effectiveness are being sought. The aim was to assess if neutrophil-to-lymphocyte, eosinophil-to-lymphocyte and platelet-to-lymphocyte ratios may predict outcomes of biologic therapy for severe asthma. METHODS: Retrospective, single-center study including severe asthma patients treated with three different biologics. The blood ratios were assessed at initiation of treatment (point 0) and after six months (point 1). The chi-square test was used to analyze differences in nominal variables. Quantitative variables were compared by Student's t-test, Mann-Whitney U or Wilcoxon signed-rank tests. RESULTS: 53 patients with severe asthma were included, among them 21 patients (40%) treated with omalizumab and 32 patients (60%) with mepolizumab or benralizumab. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios did not change during six-month-course of biological treatment. Eosinophil-to-lymphocyte ratio was higher at the point 0 (p = 0.016) in the group treated with anti-eosinophils than in the omalizumab group and lower at the point 1 (p = 0.006). In the anti-eosinophil group this ratio decreased between points 0 and 1 (p < 0.001). In the omalizumab group there was an inverse correlation between the initial ratio and oral corticosteroid dose reduction (rs = -0,67). In the a/eos group there were significant correlations between initial ratio and age (rs = 0.36), and ACQ (rs = -0.4) and ACQ (rs = 0.41) measured at the point 1. CONCLUSIONS: Pretreatment eosinophil-to-lymphocyte ratio may predict oral corticosteroid dose reduction resulting from omalizumab treatment and change in quality of life and asthma control resulting from anti-IL-5 and IL-5R treatment.

Diagnostic accuracy of eosinophil-to-lymphocyte ratio and eosinophil-to-neutrophil ratio as biomarkers for differentiating between fungal and bacterial infection in necrotising otitis externa.

INTRODUCTION: Necrotizing otitis externa (NOE) is a serious, progressive, and potentially life-threatening infection of the external auditory canal, affecting soft tissue and bone. The most common organism causing NOE is Pseudomonas Aeruginosa and less common are Fungal infections. When managing a patient with NOE, a culture is taken from the EAC in order to tailor the appropriate antimicrobial treatment, however commonly, the culture is sterile. Inflammation biomarkers may be used as adjuncts to inform on the differential diagnosis and as prognostic markers. AIM: To characterize and compare values and ratios of components of the complete blood count (CBC) at admission, at patients with positive swab culture. METHODS: A retrospective study of NOE patients was conducted. We included all patients admitted between the years 2001-2023, for whom a culture swab tested positive. We compared CBC findings at hospitalization between bacteria and fungi-positive culture patients. RESULTS: Eosinophils-to-Neutrophils Ratio (ENR) was significantly lower in the fungal group compared to the bacterial group 0.023 ± 0.02 and 0.04 ± 0.03, respectively (p-value = 0.025). Eosinophils-to-Leukocyte Ratio (ELR) was significantly lower in the fungal group compared to the bacterial group 0.058 ± 0.04 and 0.12 ± 0.1 respectively (p-value = 0.009). For definition of ELR ≤ 0.1 we found that, sensitivity was 88% (95%CI = 0.679-0.979) and NPV 90% (95%CI = 0.709-0.982). For definition of ENR ≤ 0.03 sensitivity was 88% (95%CI = 0.679-0.979) and NPV 88% (95%CI = 0.679-0.979). CONCLUSION: Lower values of ELR and ENR in patients with NOE are associated with fungal infection and can serve as a tool in adjusting an appropriate antimicrobial therapy in cases of sterile or when no culture is available.

Peripheral eosinophil count and eosinophil-to-lymphocyte ratio are associated with revision sinus surgery.

PURPOSE: The aim of this study was to assess whether hematological indices of the peripheral blood are associated with revision surgery in patients with chronic rhinosinusitis (CRS) undergoing endoscopic sinus surgery (ESS). METHODS: This retrospective, cross-sectional, single-center study included 541 CRS patients that underwent ESS. Demographics and laboratory parameters were retrieved, and group comparisons were performed. We computed binary logistic regression models to associate clinical characteristics (i.e., aeroallergen allergies, asthma, presence of nasal polyps), absolute blood counts of different leukocyte types (i.e., lymphocytes, neutrophils, basophils, and eosinophils), and hematological indices of the peripheral blood [i.e., neutrophil-to-lymphocyte ratio (NLR), basophil-to-lymphocyte ratio (BLR), eosinophil-to-lymphocyte ratio (ELR), and eosinophil-to-neutrophil ratio (ENR)] with revision surgery as outcome. RESULTS: The study population included 435 primary surgeries and 106 revision cases. Patients undergoing revision ESS showed significantly higher absolute preoperative eosinophil counts (381.6 ± 265.6 per µl), ELR (0.205 ± 0.195), and ENR (0.105 ± 0.074) compared to primary cases (all p < 0.001). Binary logistic regression analysis revealed higher odds for revision surgery in patients higher in age (ß = 1.026, p < 0.001), with presence of aeroallergen allergies (ß = 1.865, p = 0.011), presence of asthma (ß = 3.731, p = 0.001), higher preoperative eosinophil counts (ß = 1.002, p < 0.001), and higher ELR (ß = 155.663, p = 0.015). CONCLUSIONS: We found that higher peripheral eosinophil count and higher ELR were associated with revision ESS in CRS patients. Preoperative assessment of hematological indices of the peripheral blood might be a valuable indicator of disease severity, thus facilitating better treatment selection.

Eosinophils to Lymphocytes Ratio (ELR) as a Potential Inflammatory Biomarker in Patients with Dual Diagnosis of Bipolar and Alcohol Use Disorders: A Retrospective Cohort Study.

Objective: It is well-established that Bipolar Disorder (BD) has comorbidity with Alcohol Use Disorder (AUD) and could present the same symptoms of an underlying diagnosis of BD, therefore delaying the proper relevant treatment. Recent studies show the occurrence of alterations in the circulating levels of inflammatory mediators in patients dealing with AUD as well as those with BD. The objective of this study is to get an assessment of whether patients with AUD and BD comorbidity [BD(+)] would present different ratios of the Complete Blood Count (CBC) in comparison with patients with AUD but without a BD comorbidity [BD(-)]. Methods: This is a retrospective study, conducted through a selection of patients files who were admitted to the psychiatric department at Hôtel-Dieu de France University Hospital in Beirut, Lebanon, between January of the year 2016 and May of the year 2021. Overall, 83 files of patients dealing with AUD were included in this study. Results: Patients with BD(+) showed a higher Eosinophils to Lymphocytes Ratio (ELR) in comparison to those with BD(-). The Receiver Operation Characteristic (ROC) analysis had an area under the curve at 0.719 with a p = .001. The cutoff value of ELR that best differentiates BD(-) from BD(+) was 0.087 (Sensitivity = 81.3%; Specificity = 63.6%). The logistic regression analysis showed that an ELR superior to 0.087 presented a statistically significant difference, exposing patients belonging to the BD(+) group (OR = 11.66; p < .001). Conclusions: Our data suggest that ELR may be a valuable, reproducible, easily accessible, and cost-effective inflammatory marker, pointing at the presence of a BD comorbidity with AUD.

The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population.

BACKGROUND: Congenital cytomegalovirus disease (cCMV) is common and can be fatal or cause severe sequelae. Circulating strains of cytomegalovirus carry a high number of variable or disrupted genes. One of these is UL146, a highly diverse gene with 14 distinct genotypes encoding a CXC-chemokine involved in viral dissemination. UL146 genotypes 5 and 6 lack the conserved ELR motif, potentially affecting strain virulence. Here, we investigate whether UL146 genotypes 5 and 6 were associated with congenital CMV infection. METHODS: Viral DNA was extracted and UL146 sequenced from 116 neonatal dried blood spots (DBS) stored in the Danish National Biobank since 1982 and linked to registered cCMV cases through a personal identifier. These sequences were compared to UL146 control sequences obtained from CMV DNA extracted from 83 urine samples from children with suspected bacterial urinary tract infections. RESULTS: Three non-ELR UL146 genotypes (5 and 6) were observed among the cases (2.6%) and two were observed among the controls (2.4%; P > 0.99). Additionally, no significant association with cCMV was found for the other 12 genotypes in a post-hoc analysis, although genotype 8 showed a tendency to be more frequent among cases with 12 observations against three (P = 0.10). All fourteen genotypes were found to have little intra-genotype variation. Viral load, gender, and sample age were not found to be associated with any particular UL146 genotype. CONCLUSIONS: No particular UL146 genotype was associated with cCMV in this nationwide retrospective case-control study. Associations between CMV disease and disrupted or polymorph CMV genes among immunosuppressed people living with HIV/AIDS and transplant recipients should be investigated in future studies.

CXCL3 Signaling in the Tumor Microenvironment.

Cancer progression is driven, to a large extent, by the action of immune cells that have been recruited to tumor sites through interactions between chemokines and their receptors. Chemokines of the CXC subfamily are secreted by both tumor and non-tumor cells within the microenvironment of the tumor, where they induce either antitumor or protumor activity that fosters either clearance or progression of the tumor, respectively. Understanding the nature of these interactions is important to envisage novel approaches targeting the essential components of the tumor microenvironment, increasing the odds for favorable patient outcomes. In this chapter we describe the involvement of the chemokine (C-X-C motif) ligand 3 (CXCL3) in the human tumor microenvironment and its effects on immune and non-immune cells. Because of the limited data on the CXCL3 signaling in the tumor microenvironment, we extend the review to other members of the CXC subfamily of chemokines. This review also addresses the future trends or directions for therapeutic interventions that target signaling pathways used by these molecules in the tumor microenvironment.

New pre-treatment eosinophil-related ratios as prognostic biomarkers for survival outcomes in endometrial cancer.

BACKGROUND: Systemic inflammation has long been related with adverse survival outcomes in cancer patients, and its biomarkers, such as the Neutrophil-to-Lymphocyte Ratio (NLR), are recognized as poor prognostic indicators. However, the role of eosinophils in this field has been largely overlooked. Here, we describe two new pre-treatment biomarkers, expressed as Eosinophil-to-Lymphocytes Ratio (ELR) and Eosinophil*Neutrophil-to-Lymphocytes ratio (ENLR), and we analyse their impact on prognosis of endometrial cancer (EC) patients. METHODS: A total of 163 consecutive patients diagnosed with EC and treated with postoperative radiotherapy +/- chemotherapy in our institution from January 2011 to December 2015 were evaluated. The cohort was divided in two groups applying the cut-off value of 0.1 and 0.5 according to ROC curve for pre-treatment ELR and ENLR, respectively. After patients' stratification according to the ESMO-ESGO-ESTRO modified risk assessment, subgroup analyses were conducted. RESULTS: Higher values of ELR and ENLR were associated with worse OS (p = 0.004 and p = 0.010, respectively). On univariate analysis, the factors associated with shorter OS were ELR ≥ 0.1 (HR = 2.9, p = 0.017), ENLR ≥ 0.5 (HR = 3.0, p = 0.015), advanced FIGO stage (HR = 3.4, p = 0.007), endometrioid histology (HR = 0.26, p = 0.003) and ESMO-ESGO-ESTRO high-risk (HR = 10.2, p = 0.023). On multivariate Cox regression, higher ELR and ENLR were independently associated with a worse outcome adjusted for the standardly applied prognostic factors. CONCLUSIONS: Increased values of ELR and ENLR portend worse OS in EC, especially in patients classified by the ESMO-ESGO-ESTRO guidelines as a high-risk group. To our best knowledge, this is the first report describing eosinophils-related ratios as prognostic biomarkers in malignant tumours.

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani: A HOUSEKEEPING PROTEIN TRANSLATION ENZYME AND A MIMIC OF HOST CHEMOKINE.

Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes essential for protein synthesis. Apart from their parent aminoacylation activity, several aaRSs perform non-canonical functions in diverse biological processes. The present study explores the twin attributes of Leishmania tyrosyl-tRNA synthetase (LdTyrRS) namely, aminoacylation, and as a mimic of host CXC chemokine. Leishmania donovani is a protozoan parasite. Its genome encodes a single copy of tyrosyl-tRNA synthetase. We first tested the canonical aminoacylation role of LdTyrRS. The recombinant protein was expressed, and its kinetic parameters were determined by aminoacylation assay. To study the physiological role of LdTyrRS in Leishmania, gene deletion mutations were attempted via targeted gene replacement. The heterozygous mutants showed slower growth kinetics and exhibited attenuated virulence. LdTyrRS appears to be an essential gene as the chromosomal null mutants did not survive. Our data also highlights the non-canonical function of L. donovani tyrosyl-tRNA synthetase. We show that LdTyrRS protein is present in the cytoplasm and exits from the parasite cytoplasm into the extracellular medium. The released LdTyrRS functions as a neutrophil chemoattractant. We further show that LdTyrRS specifically binds to host macrophages with its ELR (Glu-Leu-Arg) peptide motif. The ELR-CXCR2 receptor interaction mediates this binding. This interaction triggers enhanced secretion of the proinflammatory cytokines TNF-α and IL-6 by host macrophages. Our data indicates a possible immunomodulating role of LdTyrRS in Leishmania infection. This study provides a platform to explore LdTyrRS as a potential target for drug development.

Nine things to know about elicitins.

888 I. 888 II. 889 III. 889 IV. 889 V. 891 VI. 891 VII. 891 VIII. 892 IX. 892 X. 893 XI. 893 893 References 893 SUMMARY: Elicitins are structurally conserved extracellular proteins in Phytophthora and Pythium oomycete pathogen species. They were first described in the late 1980s as abundant proteins in Phytophthora culture filtrates that have the capacity to elicit hypersensitive (HR) cell death and disease resistance in tobacco. Later, they became well-established as having features of microbe-associated molecular patterns (MAMPs) and to elicit defences in a variety of plant species. Research on elicitins culminated in the recent cloning of the elicitin response (ELR) cell surface receptor-like protein, from the wild potato Solanum microdontum, which mediates response to a broad range of elicitins. In this review, we provide an overview on elicitins and the plant responses they elicit. We summarize the state of the art by describing what we consider to be the nine most important features of elicitin biology.

Biocompatible ELR-Based Polyplexes Coated with MUC1 Specific Aptamers and Targeted for Breast Cancer Gene Therapy.

The search for new and biocompatible materials with high potential for improvement is a challenge in gene delivery applications. A cell type specific vector made of elastin-like recombinamer (ELR) and aptamers has been specifically designed for the intracellular delivery of therapeutic material for breast cancer therapy. A lysine-enriched ELR was constructed and complexed with plasmid DNA to give positively charged and stable polyplexes. Physical characterization of these polyplexes showed a particle size of around 140 nm and a zeta potential of approximately +40 mV. The incorporation of MUC1-specific aptamers into the polyplexes resulted in a slight decrease in zeta potential but increased cell transfection specificity for MCF-7 breast cancer cells with respect to a MUC1-negative tumor line. After showing the transfection ability of this aptamer-ELR vector which is facilitated mainly by macropinocytosis uptake, we demonstrated its application for suicide gene therapy using a plasmid containing the gene of the toxin PAP-S. The strategy developed in this work about using ELR as polymeric vector and aptamers as supplier of specificity to deliver therapeutic material into MUC1-positive breast cancer cells shows promising potential and continues paving the way for ELRs in the biomedical field.

Assessment of ELR, PLR, NLR and BLR Ratios during Omalizumab Treatment of Chronic Spontaneous Urticaria.

Background: There is a need for searching for biomarkers indicating patients who will benefit the most from treatment with omalizumab for chronic spontaneous urticaria (CSU). The aim of this study was to assess whether the eosinophil/neutrophil/platelet/basophil-to-lymphocyte ratio (ELR, NLR, PLR, BLR) may predict the response to omalizumab treatment of chronic spontaneous urticaria. Methods: A retrospective data analysis of CSU patients treated s-c with 300 mg of omalizumab every four weeks under the drug program was carried out. NLR, ELR, PLR and BLR, DLQI, UAS-7, CRP, anti-TPO and tIgE were assessed before (V0) and after three (V3) and six months (V6) of treatment. Results: Among 52 patients with CSU, 21 were responders, 24 were partially responders and 6 were non-responders to treatment with 300 mg omalizumab every four weeks. An amount of 18 patients had features of type I autoallergic CSU (CSUaiTI) and 34 patients had autoimmunity type IIb CSU with mast cell-directed activating autoantibodies (CSUaiTIIb). NLR, ELR, PLR and BLR indices did not change during a six-month-course of biological treatment. Initial values of ELR and BLR were significantly correlated with the initial tIgE level and anti-TPO/IgE ratio. Initial values of NLR, ELR and BLR were significantly correlated with initial CRP. Comparisons between type I autoallergic CSU (CSUaiTI) and autoimmunity type IIb CSU (CSUaiTIIb) revealed that the absolute number and percentage of eosinophils, basophils, BLR and tIgE were significantly higher in type CSUaiTI and anti-TPO and anti-TPO/IgE were significantly lower in type CSUaiTI. Conclusions: NLR, ELR, PLR and BLR do not change significantly during six months of omalizumab treatment and do not appear to be useful in predicting its efficacy.

EMR Combined with CRB-65 Superior to CURB-65 in Predicting Mortality in Patients with Community-Acquired Pneumonia.

Background: Data about eosinophil-to-lymphocyte ratio (ELR) and eosinophil-to-monocyte ratio (EMR) in patients with community-acquired pneumonia (CAP) are rare. We aimed to evaluate the role of EMR and ELR in predicting disease severity and mortality in patients with CAP. Methods: A total of 454 patients (76 with severe CAP (SCAP), 378 with non-SCAP) were enrolled from November 18, 2020, and November 21, 2021. Laboratory examination on day 1 after admission was measured. The ELR and EMR values were calculated for patients. Propensity score matching (PSM) was performed to balance potential confounding factors. Binary logistic regression model was fitted to identify the potential risk factors for disease severity and Cox proportional hazards regression model analysis for mortality in CAP. Receiver operating characteristic (ROC) analysis was performed to distinguish disease severity and mortality. Results: EMR and ELR at admission were significantly lower in SCAP patients than in non-SCAP patients (P<0.001). EMR < 0.018 ([OR] = 12.104, 95% CI: 4.970-29.479), neutrophil (NEU) ([OR]=1.098, 95% CI:1.005-1.199), and age ([OR]=1.091, 95% CI:1.054-1.130) were independent risk factors for disease severity of CAP. EMR < 0.032 ([HR] = 5.816, 95% CI: 1.704-9.848) was an independent predictor of in-hospital mortality. Combining EMR or ELR with CRB-65 improved the overall accuracy of disease severity prediction (AUC from 0.894 to 0.937), the same as CURB-65. The area under the curve of EMR (AUC=0.704; 95% CI: 0.582-0.827) to predict in-hospital mortality was higher than that of CURB-65 (AUC=0.619; 95% CI: 0.484-0.754). Otherwise, EMR combined with CRB-65 (AUC=0.721; 95% CI: 0.592-0.851) had significantly higher diagnostic accuracy for in-hospital mortality than that of CURB-65 alone. Conclusion: EMR combined with CRB-65 was superior to CURB-65 in predicting mortality in patients with CAP. This new combination was simpler and easier to obtain for physicians in clinics or admission, and it was more convenient for early recognition of patients with poor prognoses.

Altitude explains insignificant autumn phenological changes across regions with large topography relief in the Tibetan Plateau.

The start of the growing season (SGS) and the end of the growing season (EGS) are widely employed in global change studies to represent the spring and autumn phenology, respectively. Despite the Tibetan Plateau (TP) experiencing significant warming in recent decades, EGS has exhibited only slight changes. Previous studies have concentrated on exploring the environmental regulation of phenology, ignoring the distinctive influences of elevation. Therefore, a more in-depth investigation into the underlying mechanism is warranted. In this study, we investigate the variability of EGS among alpine vegetation regions at different elevations and conduct an analysis based on satellite data. Phenology data of alpine vegetation are extracted from SPOT NDVI dataset spanning from 1999 to 2018, using a piecewise-logistic-maximum-ratio method. We analyze the factors influencing EGS trends at different elevations. The results show that the overall insignificant variation in EGS is mainly attributed to altitude. With the altitude increasing, the annual mean EGS experiences a delay of 0.28 days/100 m below 3500 m, while it advances by 0.2 days/100 m above 3500 m. The opposing shift in elevation below and above 3500 m leads to this counteraction. Elevation emerges as the predominant factor influencing EGS trends, explaining the highest variations (38 %), followed by SGS (22 %) and precipitation (22 %). The elevation effect is most pronounced in areas with substantial topography fluctuations. Moreover, the elevation lapse rate of EGS (ELR_EGS) exhibits an opposite trend with growing season (GS) temperature and a similar trend with GS precipitation between the regions below and above 3500 m, ultimately linking to this counteraction. This study underscores elevation is a critical regulator of vegetation EGS responses to climatic changes over the TP, revealing significant spatial heterogeneities in these responses.

CXC ELR-Positive Chemokines as Diagnostic and Prognostic Markers for Breast Cancer Patients.

As the most common type of malignant lesison, breast cancer is a leading challenge for clinicians. Currently, diagnosis is based on self-examination and imaging studies that require confirmation by tissue biopsy. However, there are no easily accessible diagnostic tools that can serve as diagnostic and prognostic markers for breast cancer patients. One of the possible candidates for such markers is a group of chemokines that are closely implicated in each stage of tumorigenesis. Many researchers have noted the potential of this molecule group to become tumor markers and have tried to establish their clinical utility. In this work, we summarize the results obtained by scientists on the usefulness of the ELR-positive CXC group of chemokines in ancillary diagnosis of breast cancer.

Comparison of Inflammatory Markers for Prediction of Recurrence of Nasal Polyp after Functional Endoscopy Sinus Surgery.

The study was carried out to correlate the inflammatory markers (NLR, ELR, PLR) before and after endoscopic sinus surgery and their role in the prediction of recurrent nasal polyps. This was a hospital-based observational study carried out the 43 patients, aged between 18-45 years, admitted to the department of ENT with CRSwNP and underwent endoscopic sinus surgery. NLR, ELR & PLR values were compared for each patient and calculated from complete blood counts taken before and after surgery follow-up period at post-op 1st week, 3rd week, 3rd month, and 6th month. In our study, 12 out of 43 patients who underwent ESS showed recurrence. The mean value of ELR was higher in the pre-operative and post-operative 1st week in recurrent nasal polyp patients than in non-recurrent nasal polyps. (p-value < 0.05) but there were no significant changes in ELR values in subsequent follow-ups. There were no significant changes in NLR & PLR in the pre-operative and post-operative periods. Although recurrence was common in CRSwNP after endoscopic sinus surgery. Inflammatory markers could be used to predict the chances of recurrence. In our study, ELR is a better parameter than NLR and PLR in the assessment of the chance of recurrence.

An artificially designed elastin-like recombinant polypeptide improves aging skin.

BACKGROUND: As a substrate for cell growth, elastin can promote the regeneration and remodeling of the epidermis, which plays an important role in delaying skin aging. However, elastin proteins are more than 700 amino acids long and cannot be absorbed through the skin, which prevents the direct utilization of elastin in the prevention and treatment of aging skin. METHODS: We designed an elastin-like recombinant polypeptide (ELR) which could be absorbed through the skin based on the property of hexapeptide VGVAPG. Thirty healthy Chinese Han female participants which met the criteria were enrolled in this study and all of them completed the tests including elasticity, tightness, and wrinkle detection. The participants used this polypeptide for 4 weeks and were tested in three visits: one day before trial started (D0), and 14 and 28 days after the trial (D14 and D28, respectively). Paired t-tests or Wilcoxon signed-rank tests for non-parametric measures were used to determine the difference between D0 and D14, or D0 and D28. RESULTS: The skin elasticity level in the thirty participants was significantly increased after using ELR for 28 days (P=0.024), and the average value of skin firmness (Uf) declined from 3.313 (D0) to 3.292 (D14) and 3.265 (D28), although there was no statistically significant difference between treatment and pre-treatment. Furthermore, the wrinkle count (D14: P<0.001; D28: P<0.001), wrinkles volume (D14: P<0.001; D28: P=0.008), and wrinkles area (D14: P<0.001; D28: P<0.001) of Crow's feet were significantly improved by using ELR for 14 days or 28 days. CONCLUSION: Continuous use of ELR could significantly improve skin elasticity and reduce wrinkles.

Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas.

Medulloblastoma (MB) is the most common and aggressive paediatric brain tumour. Although the cure rate can be as high as 70%, current treatments (surgery, radio- and chemotherapy) excessively affect the patients' quality of life. Relapses cannot be controlled by conventional or targeted treatments and are usually fatal. The strong heterogeneity of the disease (four subgroups and several subtypes) is related to innate or acquired resistance to reference treatments. Therefore, more efficient and less-toxic therapies are needed. Here, we demonstrated the efficacy of a novel inhibitor (C29) of CXCR1/2 receptors for ELR+CXCL cytokines for the treatment of childhood MB. The correlation between ELR+CXCL/CXCR1/2 expression and patient survival was determined using the R2: Genomics Analysis and Visualization platform. In vitro efficacy of C29 was evaluated by its ability to inhibit proliferation, migration, invasion, and pseudo-vessel formation of MB cell lines sensitive or resistant to radiotherapy. The growth of experimental MB obtained by MB spheroids on organotypic mouse cerebellar slices was also assayed. ELR+CXCL/CXCR1/2 levels correlated with shorter survival. C29 inhibited proliferation, clone formation, CXCL8/CXCR1/2-dependent migration, invasion, and pseudo-vessel formation by sensitive and radioresistant MB cells. C29 reduced experimental growth of MB in the ex vivo organotypic mouse model and crossed the blood-brain barrier. Targeting CXCR1/2 represents a promising therapeutic strategy for the treatment of paediatric MB in first-line treatment or after relapse following conventional therapy.

Stimulated expression of ELR+ chemokines, VEGFA and TNF-AIP3 promote mycobacterial dissemination in extrapulmonary tuberculosis patients and Cavia porcellus model of tuberculosis.

Pathogenic mycobacteria induce and accelerate blood vessel formation driven by extensive inflammation during granuloma formation, which is a central feature of mycobacterial pathogenesis. Tumor necrosis factor-alpha (TNF-α) enhances the expression of vascular endothelial growth factor (VEGF) and glutamic acid-leucine-arginine (ELR+) chemokines, which are potent inducers of vascularization. Most of the reported research work contends that VEGF growth factor induces neovascularization in human tuberculosis (TB) patients, but the evidence is inconclusive. Considerable ambiguity exists concerning the factors responsible for miliary tuberculosis. To identify such factors, we proposed an alternative explanation that could be found in miliary tuberculosis (MTB) cases. We performed a comparative analysis of angiogenic factors TNF-α, VEGF, and angiogenic ELR+ CXC and CC chemokine ligands in extrapulmonary tuberculosis (EPTB) and pulmonary tuberculosis (PTB) patients. To observe the relationship of these factors with the severity of bacterial burden, guinea pigs were infected with Mycobacterium tuberculosis (M.tb) and levels of the angiogenic factors were examined at different time intervals. Expression of these factors also exhibited a significant positive correlation with bacterial burden in other organs like the spleen, liver, and lymph nodes. We demonstrated statistical data on bacterial burden at different time points following the dissemination of infection in guinea pigs. In this study, we observed that there was a stimulated increase in the expression of ELR+ chemokines and VEGF in EPTB patients as compared to PTB patients. Following increased dissemination, the host immune response clears bacteria from the lungs during disease progression in guinea pigs.

Revision ptosis surgery for under-correction after Müller muscle conjunctival resection.

INTRODUCTION: Müller muscle conjunctival resection (MMCR) may be more likely to lead to under- rather than over-correction. The choice of revision surgery is not clearly defined. METHODS: MMCR patients were included if the post-operated eyelid(s) demonstrated margin reflex distance-1 (MRD1) less than 3.5 mm, or if MRD1 asymmetry was greater than 0.5 mm, and if they underwent subsequent revision surgery. MRD1 was the primary outcome measure and complications were secondary outcome measures. Two groups were defined: patients who underwent MMCR then repeat MMCR (M-M) and those who underwent MMCR followed by external levator resection (ELR) surgery (M-L). RESULTS: 18 eyelids (16 patients) were included, 12 in M-M and 6 in M-L. Mean (SD) preoperative MRD1 was 1.84 mm (0.97), range -0.41 to 3.39 mm. There was no difference (p = 0.70) in preoperative MRD1 between M-M and M-L. In the M-M group, mean (SD) MRD1 was 1.77 mm (1.12) preoperatively, 2.35 mm (0.66) after the first surgery, and 3.44 mm (0.31) after revision. Mean MRD1 was significantly higher after revision, compared to preoperatively (p < 0.05) and after first surgery (p < 0.05). In the M-L group (n = 6), mean (SD) MRD1 was 1.98 mm (0.90) preoperatively, 1.99 mm (0.56) after the first surgery and 3.44 mm (1.24) after revision. The difference between preoperative and post revision surgery MRD1 was significant (p < 0.05). CONCLUSIONS: For patients with insufficient elevation of MRD1 or with asymmetry after MMCR, revision by MMCR or by ELR are both reasonable options.

Cancer-associated adipocytes promote the invasion and metastasis in breast cancer through LIF/CXCLs positive feedback loop.

Cancer-associated adipocytes (CAAs), which are adipocytes transformed by cancer cells, are of great importance in promoting the progression of breast cancer. However, the underlying mechanisms involved in the crosstalk between cancer cells and adipocytes are still unknown. Here we report that CAAs and breast cancer cells communicate with each other by secreting the cytokines leukemia inhibitory factor (LIF) and C-X-C subfamily chemokines (CXCLs), respectively. LIF is a pro-inflammatory cytokine secreted by CAAs, which promotes migration and invasion of breast cancer cells via the Stat3 signaling pathway. The activation of Stat3 induced the secretion of glutamic acid-leucine-arginine (ELR) motif CXCLs (CXCL1, CXCL2, CXCL3 and CXCL8) in tumor cells. Interestingly, CXCLs in turn activated the ERK1/2/NF-κB/Stat3 signaling cascade to promote the expression of LIF in CAAs. In clinical breast cancer pathology samples, the up-regulation of LIF in paracancerous adipose tissue was positively correlated with the activation of Stat3 in breast cancer. Furthermore, we verified that adipocytes enhanced lung metastasis of breast cancer cells, and the combination of EC330 (targeting LIF) and SB225002 (targeting C-X-C motility chemokine receptor 2 (CXCR2)) significantly reduced lung metastasis of breast cancer cells in vivo. Our findings reveal that the interaction of adipocytes with breast cancer cells depends on a positive feedback loop between the cytokines LIF and CXCLs, which promotes breast cancer invasion and metastasis.