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Despite proven scientific quality of menstrual blood mesenchymal cells, research and science output using those cells is still incipient, which suggests there is a resistance to the study of this type of cell by scientists, and a lack of attention to its potential for cell therapy, regenerative medicine and bioengineering. This study analyzes the literature about the menstrual blood mesenchymal stromal/stem cells (mbMSC) on the PubMed database between 2008–2020 and the social attention it received on Twitter. A comparative analysis showed that mbMSC accounts for a very small portion of mesenchymal cell research (0.25%). Most first authors are women (53.2%), whereas most last authors are men (63.74%), reinforcing an already known, and still significant, gender gap between last and corresponding authors. Menstrual blood tends to be less used in experiments and its scientific value tends to be underestimated, which brings gender bias to a technical and molecular level. Although women are more positive in the mbMSC debate on Twitter, communication efforts toward visibility and public interest in menstrual cells has room to grow. [ABSTRACT FROM AUTHOR]

Object detection technology has been widely used in medical field, such as detecting the images of blood cell to count the changes and distribution for assisting the diagnosis of diseases. However, detecting small objects is one of the most challenging and important problems especially in medical scenarios. Most of the objects in medical images are very small but influential. Improving the detection performance of small objects is a very meaningful topic for medical detection. Current researches mainly focus on the extraction of small object features and data augmentation for small object samples, all of these researches focus on extracting the feature space of small objects better. However, in the training process of a detection model, objects of different sizes are mixed together, which may interfere with each other and affect the performance of small object detection. In this paper, we propose a method called pixel level balancing (PLB), which takes into account the number of pixels contained in the detection box as an impact factor to characterize the size of the inspected objects, and uses this as an impact factor. The training loss of each object of different size is adjusted by a weight dynamically, so as to improve the accuracy of small object detection. Finally, through experiments, we demonstrate that the size of objects in object detection interfere with each other. So that we can improve the accuracy of small object detection through PLB operation. This method can perform well with blood cell detection in our experiments. [ABSTRACT FROM AUTHOR]

Background: Infusion of mesenchymal stromal cells (MSCs) has been proposed as immune-modulatory therapy in solid organ transplantation. The use of allogenic MSCs could improve standardization and allow for direct availability of the product. Method: The nonrandomized phase Ib Neptune clinical trial provided safety and feasibility data on the use of allogenic bone-marrow-derived MSCs, infused in 10 patients at week 25 and 26 post kidney transplantation. Here, we performed detailed analysis on the peripheral blood immune cell composition of these patients up to 52 weeks post transplantation. We used a 40 marker antibody panel with mass cytometry to assess potential effects of MSC therapy on the immune system. Results: We showed minor changes in major immune lineages at week 27, 34 and 52 post kidney transplantation after MSC infusion at week 25 and week 26, confirming previous data with regular flow cytometry. However, in a direct comparison between pre- and post MSC infusion, as soon as 4 hours after MSC infusion, we observed a significant increase in cell numbers of B cell and T cell subsets that shared a unique expression of CD11b, CD11c, CD38, CD39, and Ki-67. Conclusion: Exploring these CD11b+CD11c+CD38+CD39+Ki-67+ B cells and T cells in the context of MSC infusion after kidney transplantation may be a promising avenue to better understand the immunological effects of MSC therapy. [ABSTRACT FROM AUTHOR]

Background: Immunotherapeutic approaches, including immune checkpoint inhibitor (ICI) therapy, are increasingly recognized for their potential. Despite notable successes, patient responses to these treatments vary significantly. The absence of reliable predictive and prognostic biomarkers hampers the ability to foresee outcomes. This meta-analysis aims to evaluate the predictive significance of circulating myeloid-derived suppressor cells (MDSC) in patients with solid tumors undergoing ICI therapy, focusing on progression-free survival (PFS) and overall survival (OS). Methods: A comprehensive literature search was performed across PubMed and EMBASE from January 2007 to November 2023, utilizing keywords related to MDSC and ICI. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) directly from the publications or calculated them based on the reported data. A hazard ratio greater than 1 indicated a beneficial effect of low MDSC levels. We assessed heterogeneity and effect size through subgroup analyses. Results: Our search yielded 4,023 articles, of which 17 studies involving 1,035 patients were included. The analysis revealed that patients with lower levels of circulating MDSC experienced significantly improved OS (HR=2.13 [95% CI 1.51-2.99]) and PFS (HR=1.87 [95% CI 1.29-2.72]) in response to ICI therapy. Notably, heterogeneity across these outcomes was primarily attributed to differences in polymorphonuclear MDSC (PMN-MDSC) subpopulations and varying cutoff methodologies used in the studies. The monocytic MDSC (M-MDSC) subpopulation emerged as a consistent and significant prognostic marker across various subgroup analyses, including ethnicity, tumor type, ICI target, sample size, and cutoff methodology. Conclusions: Our findings suggest that standardized assessment of MDSC, particularly M-MDSC, should be integral to ICI therapy strategies. These cells hold the promise of identifying patients at risk of poor response to ICI therapy, enabling tailored treatment approaches. Further research focusing on the standardization of markers and validation of cutoff methods is crucial for integrating MDSC into clinical practice. [ABSTRACT FROM AUTHOR]

Background: Kidney cancer is a prevalent malignancy with an increasing incidence worldwide. Blood cell indices and inflammation-related markers have shown huge potential as biomarkers for predicting cancer incidences, but that is not clear in kidney cancer. Our study aims to investigate the correlations of blood cell indices and inflammation-related markers with kidney cancer risk. Methods: We performed a population-based cohort prospective analysis using data from the UK Biobank. A total of 466,994 participants, free of kidney cancer at baseline, were included in the analysis. The hazard ratios (HRs) and 95% confidence intervals (CIs) for kidney cancer risk were calculated using Cox proportional hazards regression models. Restricted cubic spline models were used to investigate nonlinear longitudinal associations. Stratified analyses were used to identify high-risk populations. The results were validated through sensitivity analyses. Results: During a mean follow-up of 12.4 years, 1,710 of 466,994 participants developed kidney cancer. The Cox regression models showed that 13 blood cell indices and four inflammation-related markers were associated with kidney cancer incidence. The restricted cubic spline models showed non-linear relationships with kidney cancer. Finally, combined with stratified and sensitivity analyses, we found that the mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), platelet distribution width (PDW), systemic immune-inflammation index (SII), and product of platelet count and neutrophil count (PPN) were related to enhanced kidney cancer risk with stable results. Conclusion: Our findings identified that three blood cell indices (MCHC, RDW, and PDW) and two inflammation-related markers (SII and PPN) were independent risk factors for the incidence of kidney cancer. These indexes may serve as potential predictors for kidney cancer and aid in the development of targeted screening strategies for at-risk individuals. [ABSTRACT FROM AUTHOR]

Background: Progressive decline of allograft function leads to premature graft loss. Forkhead box P3 (FOXP3), a characteristic gene of T-regulatory cells, is known to be essential for auto-antigen tolerance. We assessed the hypothesis that low FOXP3 mRNA splice variant levels in peripheral blood cells early after transplantation are associated with progressive allograft injury. Methods: Blood samples were prospectively collected from 333 incident kidney transplant recipients on the first and 29th postoperative day. We used quantitative polymerase chain reaction to determine transcripts of 3 isotypes of FOXP3 splice variants, including pre-mature FOXP3 and full length FOXP3 (FOXP3fl). We investigated the association between FOXP3 splice variant levels and the declines in estimated glomerular filtration rate (eGFR) of more than 5ml/min/1.73m2 within the first-year post-transplant using logistic regression. Results: We observed lower FOXP3fl levels in recipients with declining eGFR (N = 132) than in recipients with stable eGFR (N = 201), (logarithmic value -4.13 [IQR -4.50 to -3.84] vs -4.00 [4.32 to -3.74], p=0.02). In ad hoc analysis pre-transplant FOXP3fl levels were similar in both groups. The association between FOXP3fl and declining eGFR was confirmed by multivariable analysis adjusted for potential confounding factors (Odds Ratio 0.51, 95% confidence interval 0.28 to 0.91: p=0.02). When stratifying FOXP3fl levels into quartiles, recipients with lower day1 FOXP3fl had the highest rate of declining eGFR (p=0.04). Conclusion: Low FOXP3fl splice variant levels at the first postoperative day in kidney transplant recipients were associated with severe decline of eGFR, a wellknown surrogate for hard endpoints. [ABSTRACT FROM AUTHOR]

Introduction: About 50% of cutaneous melanoma (CM) patients present activating BRAF mutations that can be effectively targeted by BRAF inhibitors (BRAFi). However, 20% of CM patients exhibit intrinsic drug resistance to BRAFi, while most of the others develop adaptive resistance over time. The mechanisms involved in BRAFi resistance are disparate and globally seem to rewire the cellular signaling profile by up-regulating different receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR). RTKs inhibitors have not clearly demonstrated anti-tumor activity in BRAFi resistant models. To overcome this issue, we wondered whether the shared up-regulated RTK phenotype associated with BRAFi resistance could be exploited by using immune weapons as the antibody-dependent cell cytotoxicity (ADCC)-mediated effect of anti-RTKs antibodies, and kill tumor cells independently from the mechanistic roots. Methods and results: By using an in vitro model of BRAFi resistance, we detected increased membrane expression of EGFR, both at mRNA and protein level in 4 out of 9 BRAFi-resistant (VR) CM cultures as compared to their parental sensitive cells. Increased EGFR phosphorylation and AKT activation were observed in the VR CM cultures. EGFR signaling appeared dispensable for maintaining resistance, since small molecule-, antibody- and CRISPR-targeting of EGFR did not restore sensitivity of VR cells to BRAFi. Importantly, immune-targeting of EGFR by the anti-EGFR antibody cetuximab efficiently and specifically killed EGFR-expressing VR CM cells, both in vitro and in humanized mouse models in vivo, triggering ADCC by healthy donors’ and patients’ peripheral blood cells. Conclusion: Our data demonstrate the efficacy of immune targeting of RTKs expressed by CM relapsing on BRAFi, providing the proof-of-concept supporting the assessment of anti-RTK antibodies in combination therapies in this setting. This strategy might be expected to concomitantly trigger the crosstalk of adaptive immune response leading to a complementing T cell immune rejection of tumors. [ABSTRACT FROM AUTHOR]

γδ T cells are important components of the immune system due to their ability to elicit a fast and strong response against infected and transformed cells. Because they can specifically and effectively kill target cells in an MHC independent fashion, there is great interest to utilize these cells in anti-tumor therapies where antigen presentation may be hampered. Since only a small fraction of T cells in the blood or tumor tissue are γδ T cells, they require extensive expansion to allow for fundamental, preclinical and ex vivo research. Although expansion protocols can be successful, most are based on depletion of other cell types rather than γδ T cell specific isolation, resulting in unpredictable purity of the isolated fraction. Moreover, the primary focus only lies with expansion of Vd2+ T cells, while Vd1+ T cells likewise have anti-tumor potential. Here, we investigated whether γδ T cells directly isolated from blood could be efficiently expanded while maintaining function. γδ T cell subsets were isolated using MACS separation, followed by FACS sorting, yielding >99% pure γδ T cells. Isolated Vd1+ and Vd2+ T cells could effectively expand immediately after isolation or upon freeze/thawing and reached expansion ratios between 200 to 2000-fold starting from varying numbers using cytokine supported feeder stimulations. MACS/FACS isolated and PHA stimulated γδ T cells expanded as good as immobilized antibody mediated stimulated cells in PBMCs, but delivered purer cells. After expansion, potential effector functions of γδ T cells were demonstrated by IFN-g, TNF-a and granzyme B production upon PMA/ionomycin stimulation and effective killing capacity of multiple tumor cell lines was confirmed in killing assays. In conclusion, pure γδ T cells can productively be expanded while maintaining their anti-tumor effector functions against tumor cells. Moreover, γδ T cells could be expanded from low starting numbers suggesting that this protocol may even allow for expansion of cells extracted from tumor biopsies. [ABSTRACT FROM AUTHOR]

Background: Neutrophil extracellular traps (NETs) play a key role in thrombus formation in patients with coronavirus disease 2019 (COVID-19). However, the existing detection and observation methods for NETs are limited in their ability to provide quantitative, convenient, and accurate descriptions of in situ NETs. Therefore, establishing a quantitative description of the relationship between NETs and thrombosis remains a challenge. Objective: We employed morphological observations of blood cells and statistical analyses to investigate the correlation between the NETs/neutrophilic segmented granulocyte ratio and mortality risk in patients with COVID-19. Methods: Peripheral blood samples were collected from 117 hospitalized patients with COVID-19 between November 2022 and February 2023, and various blood cell parameters were measured. Two types of smudge cells were observed in the blood and counted: lymphatic and neutral smudge cells. Statistical data analysis was used to establish COVID-19 mortality risk assessment indicators. Results: Morphological observations of neutrophilic smudge cells revealed swelling, eruption, and NETs formation in the neutrophil nuclei. Subsequently, the NETs/neutrophilic segmented granulocyte ratio (NNSR) was calculated. A high concentration of NETs poses a fatal risk for thrombus formation in patients. Statistical analysis indicated that a high NNSR was more suitable for evaluating the risk of death in patients with COVID-19 compared to elevated fibrinogen (FIB) and D-dimer (DD) levels. Conclusion: Observing blood cell morphology is an effective method for the detection of NETs, NNSR are important markers for revealing the mortality risk of patients with COVID-19. [ABSTRACT FROM AUTHOR]

Background: There is a growing need for immunological assays to test toxic and modulatory effects of chemicals. The assays should be easy to use, reproducible and superior to cell line-based assays. We have therefore developed a comprehensive portfolio of assays based on primary human blood cells that are suitable for testing chemical effects. Methods: The flow cytometry-based assays were designed to target a wide range of human peripheral blood mononuclear cells and whole blood, including T cells, NK cells, B cells, basophils and innate-like T cells such as gdT, MAIT and NKT cells. We have selected a set of activation markers for each immune cell, e.g: CD154 (T cells), CD137, CD107a (NK cells), CD63 (basophils), CD69, CD83 (B cells), CD69, IFN-g (MAIT cells) and we selected cell specific stimuli: aCD3 antibodies (T cells); E. coli and cytokines IL-12/15/ 18 (MAIT cells); CpG ODN2006, R848 or aCD40 antibodies (B cells), fMLP or aFcϵR1 (basophils) or K562 cells (NK cells). Results: By selecting immune cell-specific markers and cell-specific stimuli, we were able to induce particular immune responses from the targeted immune cells. For example, the response to stimulation with anti-CD3 antibodies was in 36.8% of CD107a+CD8+ cells. Cytokine stimulation induced the production of IFN-g in 30% of MAIT cells. After stimulation with E. coli, around 50% of MAIT cells produced TNF. About 40% of basophils responded to aFcƐR1 stimulation. Similar activation ranges were achieved in K562-stimulated NK cells.Conclusion: Our test portfolio covers the most relevant immune cells present in human blood, providing a solid basis for in vitro toxicity and immunomodulatory testing of chemicals. By using human blood, the natural composition of cells found in the blood can be determined and the effects of chemicals can be detected at the cellular level. [ABSTRACT FROM AUTHOR]

Background: Gestational diabetes (GDM) affects approximately 14% of pregnancies globally and is associated with short- and long-term complications for both the mother and child. In addition, GDM has been linked to chronic low-grade inflammation with recent research indicating a potential immune dysregulation in pathophysiology and a disparity in regulatory T cells.Objective: This systematic review and meta-analysis aimed to determine whether there is an association between GDM and the level of Tregs in the peripheral blood.Methods: Literature searches were conducted in PubMed, Embase, and Ovid between the 7th and 14th of February 2022. The inclusion criteria were any original studies published in the English language, measuring differentiated Tregs in women with GDM compared with glucose-tolerant pregnant women. Meta-analysis was performed between comparable Treg markers. Statistical tests were used to quantify heterogeneity: τ², χ², and I². Study quality was assessed using a modified version of the Newcastle-Ottawa scale.Results: The search yielded 223 results: eight studies were included in the review and seven in the meta-analysis (GDM = 228, control = 286). Analysis of Tregs across all trimesters showed significantly lower Treg numbers in women with GDM (SMD, −0.76; 95% CI, −1.37, −0.15; I² = 90%). This was reflected in the analysis by specific Treg markers (SMD −0.55; 95% CI, −1.04, −0.07; I² = 83%; third trimester, five studies). Non-significant differences were found within subgroups (differentiated by CD4+FoxP3+, CD4+CD127−, and CD4+CD127−FoxP3) of both analyses.Conclusion: GDM is associated with lower Treg numbers in the peripheral maternal blood. In early pregnancy, there is clinical potential to use Treg levels as a predictive tool for the subsequent development of GDM. There is also a potential therapeutic intervention to prevent the development of GDM by increasing Treg populations. However, the precise mechanism by which Tregs mediate GDM remains unclear. [ABSTRACT FROM AUTHOR]

In this work, we aimed at investigating cell and tissue responses of the apple snail Pomacea canaliculata, following the inoculation of the zoonotic pathogen Mycobacterium marinum. Different doses were tested (10, 20, 65, and 100 M CFU) and the mortality rate was negligible. The histopathogenesis was followed at 4, 9, and 28 days after inoculation. Overt histopathological lesions were consistently observed after the two largest doses only. In the lung, marked hemocyte aggregations, including intravascular nodule formation, were observed within the large blood veins that run along the floor and roof of this organ. Hemocyte aggregations were found occluding many of the radial sinuses supplying the respiratory lamina. Acid-fast bacilli were contained in the different hemocyte aggregations. In addition, hemocytes were observed infiltrating the storage tissue, which makes up most of the lung wall, and the connective tissue of the mantle edge. Additionally, signs of degradation in the storage tissue were observed in the lung wall on day 28. In the kidney, nodules were formed associated with the constitutive hemocyte islets and with the subpallial hemocoelic space, in whose hemocytes the acid-fast structures were found. Electron microscopy analysis revealed the presence of bacteria-containing phagosomes within hemocytes located in the surface zone of the islets. Additionally, electron-dense spheroidal structures, which are likely remnants of digested mycobacteria, were observed in close proximity to the hemocytes' nuclei. The size attained by the hemocyte nodules varied during the observation period, but there was no clear dependence on dose or time after inoculation. Nodules were also formed subpallially. Some of these nodules showed 2-3 layers with different cellular composition, suggesting they may also form through successive waves of circulating cells reaching them. Nodular cores, including those formed intravascularly in the lung, would exhibit signs of hemocyte dedifferentiation, possibly proliferation, and death. Hemocyte congestion was observed in the hemocoelic spaces surrounding the pallial ends of the renal crypts, and the renal crypts themselves showed de-epithelization, particularly on day 28. The diverse cellular responses of P. canaliculata to M. marinum inoculation and the high resilience of this snail to the pathogen make it a suitable species for studying mycobacterial infections and their effects on cellular and physiological processes. [ABSTRACT FROM AUTHOR]

Background: The examination, counting, and classification of white blood cells (WBCs), also known as leukocytes, are essential processes in the diagnosis of many disorders, including leukemia, a kind of blood cancer characterized by the uncontrolled proliferation of carcinogenic leukocytes in the marrow of the bone. Blood smears can be chemically or microscopically studied to better understand hematological diseases and blood disorders. Detecting, identifying, and categorizing the many blood cell types are essential for disease diagnosis and therapy planning. A theoretical and practical issue. However, methods based on deep learning (DL) have greatly helped blood cell classification. Materials and Methods: Images of blood cells in a microscopic smear were collected from GitHub, a public source that uses the MIT license. An end-to-end computer-aided diagnosis (CAD) system for leukocytes has been created and implemented as part of this study. The introduced system comprises image preprocessing and enhancement, image segmentation, feature extraction and selection, and WBC classification. By combining the DenseNet-161 and the cyclical learning rate (CLR), we contribute an approach that speeds up hyperparameter optimization. We also offer the one-cycle technique to rapidly optimize all hyperparameters of DL models to boost training performance. Results: The dataset has been split into two sets: approximately 80% of the data (9,966 images) for the training set and 20% (2,487 images) for the validation set. The validation set has 623, 620, 620, and 624 eosinophil, lymphocyte, monocyte, and neutrophil images, whereas the training set has 2,497, 2,483, 2,487, and 2,499, respectively. The suggested method has 100% accuracy on the training set of images and 99.8% accuracy on the testing set. Conclusion: Using a combination of the recently developed pretrained convolutional neural network (CNN), DenseNet, and the one fit cycle policy, this study describes a technique of training for the classification of WBCs for leukemia detection. The proposed method is more accurate compared to the state of the art. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors (ICIs) only benefit a subset of cancer patients, underlining the need for predictive biomarkers for patient selection. Given the limitations of tumor tissue availability, flow cytometry of peripheral blood mononuclear cells (PBMCs) is considered a noninvasive method for immune monitoring. This study explores the use of spectrum flow cytometry, which allows a more comprehensive analysis of a greater number of markers using fewer immune cells, to identify potential blood immune biomarkers and monitor ICI treatment in non-small-cell lung cancer (NSCLC) patients. Methods: PBMCs were collected from 14 non-small-cell lung cancer (NSCLC) patients before and after ICI treatment and 4 healthy human donors. Using spectrum flow cytometry, 24 immune cell markers were simultaneously monitored using only 1 million PBMCs. The results were also compared with those from clinical flow cytometry and bulk RNA sequencing analysis. Results: Our findings showed that the measurement of CD4+ and CD8+ T cells by spectrum flow cytometry matched well with those by clinical flow cytometry (Pearson R ranging from 0.75 to 0.95) and bulk RNA sequencing analysis (R=0.80, P=1.3 x 10-4). A lower frequency of CD4+ central memory cells before treatment was associated with a longer median progression-free survival (PFS) [Not reached (NR) vs. 5 months; hazard ratio (HR)=8.1, 95% confidence interval (CI) 1.5-42, P=0.01]. A higher frequency of CD4-CD8-double-negative (DN) T cells was associated with a longer PFS (NR vs. 4.45 months; HR=11.1, 95% CI 2.2-55.0, P=0.003). ICIs significantly changed the frequency of cytotoxic CD8+PD1+ T cells, DN T cells, CD16+CD56dim and CD16+CD56- natural killer (NK) cells, and CD14+HLDRhigh and CD11c+HLADR + monocytes. Of these immune cell subtypes, an increase in the frequency of CD16+CD56dim NK cells and CD14 +HLADRhigh monocytes after treatment compared to before treatment were associated with a longer PFS (NR vs. 5 months, HR=5.4, 95% CI 1.1-25.7, P=0.03; 7.8 vs. 3.8 months, HR=5.7, 95% CI 169 1.0-31.7, P=0.04), respectively. Conclusion: Our preliminary findings suggest that the use of multicolor spectrum flow cytometry helps identify potential blood immune biomarkers for ICI treatment, which warrants further validation. [ABSTRACT FROM AUTHOR]

The epithelial to mesenchymal transition (EMT) is a fundamental developmental process essential for normal embryonic development. It is also important during various pathogenic processes including fibrosis, wound healing and epithelial cancer cell metastasis and invasion. EMT is regulated by a variety of cell signalling pathways, cell-cell interactions and microenvironmental cues, however the key drivers of EMT are transcription factors of the ZEB, TWIST and SNAIL families. Recently, novel and unexpected roles for these EMT transcription factors (EMTTFs) during normal blood cell development have emerged, which appear to be largely independent of classical EMT processes. Furthermore, EMT-TFs have also begun to be implicated in the development and pathogenesis of malignant hematological diseases such as leukemia and lymphoma, and now present themselves or the pathways they regulate as possible new therapeutic targets within these malignancies. In this review, we discuss the ZEB, TWIST and SNAIL families of EMT-TFs, focusing on what is known about their normal roles during hematopoiesis as well as the emerging and “unexpected” contribution they play during development and progression of blood cancers. [ABSTRACT FROM AUTHOR]

Objective: This study aims to assess the associations of complete blood cell count (CBC)-derived inflammatory biomarkers with the prevalence of asthma and mortality. Methods: Data was collected from the 1999-2018 National Health and Nutrition Examination Survey (NHANES). Mortality was identified using the National Death Index until December 31, 2019. The study analyzed the relationship between CBC-derived inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic inflammatory response index (SIRI), and systemic immune-inflammation index (SII), and the prevalence of asthma using multiple logistic regressions. To assess the significance of CBC-derived inflammatory biomarkers in predicting all-cause and respiratory disease mortality in asthma patients, Cox proportional regressions and the random survival forest (RSF) analysis were utilized. Results: A total of 48,305 participants were included, with a mean age of 47.27 ± 0.18 years and 49.44% male. Among them, 6,403 participants had asthma, with a prevalence of 13.28%. The all-cause and respiratory disease deaths at a median follow-up of 8.2 (4.5, 12.8) years were 929 and 137 respectively. After adjusting for confounders, the prevalence of asthma was found to be positively associated with NLR, PLR, MLR, SIRI and SII. Compared to the lowest quartile, the highest quartile of NLR (HR=1.765 [1.378-2.262]), MLR (HR=1.717 [1.316-2.241]), SIRI (HR=1.796 [1.353-2.383]) and SII (HR=1.432 [1.141-1.797]) were associated with an increased risk of all-cause mortality. These associations were more pronounced in respiratory disease mortality of asthma patients. RSF analysis showed that MLR had the highest predictive value for all-cause and respiratory disease mortality in adults with asthma. The sensitivity analysis demonstrated the stability of our results. Conclusion: The findings suggest that CBC-derived inflammatory biomarkers are associated with a higher risk of all-cause and respiratory disease mortality in adults with asthma. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a highly malignant tumor that carries a significant risk of morbidity and mortality. This type of cancer is prevalent in Asia due to the widespread presence of risk factors. Unfortunately, HCC often goes undetected until it has reached an advanced stage, making early detection and treatment critical for better outcomes. Alpha-fetoprotein (AFP) is commonly used in clinical practice for diagnosing HCC, but its sensitivity and specificity are limited. While surgery and liver transplantation are the main radical treatments, drug therapy and local interventions are better options for patients with advanced HCC. Accurately assessing treatment efficacy and adjusting plans in a timely manner can significantly improve the prognosis of HCC. Non-coding RNA gene transcription products cannot participate in protein production, but they can regulate gene expression and protein function through the regulation of transcription and translation processes. These non-coding RNAs have been found to be associated with tumor development in various types of tumors. Noncoding RNA released by tumor or blood cells can circulate in the blood and serve as a biomarker for diagnosis, prognosis, and efficacy assessment. This article explores the unique role of circulating noncoding RNA in HCC from various perspectives. [ABSTRACT FROM AUTHOR]

Dysregulation of the bone marrow niche resulting from the direct and indirect effects of HIV infection contributes to haematological abnormalities observed in HIV patients. The bone marrow niche is a complex, multicellular environment which functions primarily in the maintenance of haematopoietic stem/progenitor cells (HSPCs). These adult stem cells are responsible for replacing blood and immune cells over the course of a lifetime. Cells of the bone marrow niche support HSPCs and help to orchestrate the quiescence, self-renewal and differentiation of HSPCs through chemical and molecular signals and cell-cell interactions. This narrative review discusses the HIV-associated dysregulation of the bone marrow niche, as well as the susceptibility of HSPCs to infection by HIV. [ABSTRACT FROM AUTHOR]

In response to the increasing demand for lung transplantation, ex vivo lung perfusion (EVLP) has extended the number of suitable donor lungs by rehabilitating marginal organs. However despite an expanding use in clinical practice, the responses of the different lung cell types to EVLP are not known. In order to advance our mechanistic understanding and establish a refine tool for improvement of EVLP, we conducted a pioneer study involving single cell RNA-seq on human lungs declined for transplantation. Functional enrichment analyses were performed upon integration of data sets generated at 4 h (clinical duration) and 10 h (prolonged duration) from two human lungs processed to EVLP. Pathways related to inflammation were predicted activated in epithelial and blood endothelial cells, in monocyte-derived macrophages and temporally at 4 h in alveolar macrophages. Pathways related to cytoskeleton signaling/organization were predicted reduced in most cell types mainly at 10 h. We identified a division of labor between cell types for the selected expression of cytokine and chemokine genes that varied according to time. Immune cells including CD4+ and CD8+ T cells, NK cells, mast cells and conventional dendritic cells displayed gene expression patterns indicating blunted activation, already at 4 h in several instances and further more at 10 h. Therefore despite inducing inflammatory responses, EVLP appears to dampen the activation of major lung immune cell types, what may be beneficial to the outcome of transplantation. Our results also support that therapeutics approaches aiming at reducing inflammation upon EVLP should target both the alveolar and vascular compartments. [ABSTRACT FROM AUTHOR]

Background: There are bidirectional associations between immunological dysfunction and psychiatric symptoms. However, the associations between the levels of immune cells in the peripheral blood and psychiatric symptoms remain unclear. The present study aimed to evaluate levels of immune cells in peripheral blood in people with positive psychiatric symptoms. Methods: This retrospective study analyzed data from routine blood tests and psychopathology and sleep quality assessments. Data were compared between a group of 45 patients with de novo psychological symptoms and 225 matched controls. Results: Patients with psychiatric symptoms had higher white blood cell and neutrophil counts compared with controls. However, in a subgroup analysis, neutrophil counts were significantly higher than in controls only in patients with multiple psychiatric symptoms. Furthermore, monocyte counts were significantly higher in patients with multiple psychiatric symptoms than in controls. Further, sleep quality was lower in patients with psychiatric symptoms than in controls. Conclusion: White blood cell and neutrophil counts in the peripheral blood of patients with psychiatric symptoms were significantly higher and sleep quality was significantly lower than in controls. Participants with multiple psychiatric symptoms showed more significant differences in peripheral blood immune cell counts than other subgroups. These results provided evidence for the relationship between psychiatric symptoms, immunity, and sleep. [ABSTRACT FROM AUTHOR]

Introduction: Destruxin A (DA) is a mycotoxin isolated from the entomopathogenic fungus Metarhizium anisopliae which has demonstrated inhibitory activity against various insect species. However, the mechanism of inhibition on target sites in insects remains unknown. Methods: In this research, the dose-response relationship between DA and morphological changes in body tissues and organs of domestic silkworm, Bombyx mori, were investigated by histopathological methods to identify the target sites that responded to DA. Results and Discussion: The results showed that responses of individual tissues and organs varied with DA dosage and treatment time. At low doses (i.e., 0.01µg/g), the hemocytes were the most sensitive to DA with morphological changes apparent at 6 h after treatment. However, the muscle cells, fat body, and Malpighian tubules were unaltered. At higher doses (i.e., > 0.1µg/g), morphological changes were observed in muscle cells, fat body, and Malpighian tubules at 24 h after treatment. The results indicated that DA can be an immunosuppressant by damaging host cells like hemocytes, and at higher doses may potentially impact other physiological processes, including muscle function, metabolism, and excretion. The information presented in the current study will facilitate development of mycopesticides and novel immunosuppressants. [ABSTRACT FROM AUTHOR]

Importance: Glaucoma is the second leading cause of blindness in the world. The causal direction and magnitude of the association between blood cell traits and glaucoma is uncertain because of the susceptibility of observational studies to confounding and reverse causation. Objective: To explore whether there is a causal relationship of blood cell traits including white blood cell (WBC) count (WBCC) and its subtypes [basophil cell count (BASO), monocyte cell count (MONO), lymphocyte cell count (LYMPH), eosinophil cell count (EOS), neutrophil cell count (NEUT)], red blood cell (RBC) count (RBCC), red blood distribution width (RDW), platelet count (PLT), and plateletcrit (PCT) on glaucoma risk. Methods: A two-sample Mendelian randomization (MR) analysis was conducted. Genome-wide significant single nucleotide polymorphisms (SNPs) from published genome-wide association studies (GWAS) on human blood cell traits were utilized as exposure instruments and the dataset for outcome was from the GWAS summary data of glaucoma. In the univariable MR analysis, we examined the association between genetic evidence of blood cell traits and glaucoma. To further investigate the potential causal mechanisms underlying the observed association, we performed multivariable MR analysis with three models, taking into account the mediator effect of inflammation and oxidative stress. According to Bonferroni-corrected for the 10 exposures in 3 methods, the MR study yielded a statistically significant p-value of 0.0017. Results: Genetically BASO, PCT, LYMPH, and PLT were potentially positively associated with glaucoma in the European ancestry [BASO: Odds ratio (OR) = 1.00122, 95% confidence interval (CI), 1.00003–1.00242, p = 0.045; PCT: OR = 1.00078, 95% CI, 1.00012–1.00143, p = 0.019; LYMPH: OR = 1.00076, 95% CI, 1.00002–1.00151, p = 0.045; PLT: OR = 1.00065, 95% CI, 1.00006–1.00123, p = 0.030], There was insufficient evidence to support a causal association of MONO, NEUT, EOS, WBCC, RBCC and RDW (MONO: OR = 1.00050, p = 0.098; NEUT: OR = 1.00028, p = 0.524; EOS: OR = 1.00020, p = 0.562; WBCC: OR = 1.00008, p = 0.830; RBCC: OR = 0.99996, p = 0.920; RDW: OR = 0.99987, p = 0.734) with glaucoma. The multivariable MR with model 1, 2, and 3 demonstrated that BASO, PCT, LYMPH, and PLT were still potentially genetically associated with the risk of glaucoma. Conclusion: Our study reveals a genetic predisposition to higher LYMPH, BASO, PLT, and PCT are associated with a higher risk of glaucoma, whereas WBCC, MONO, EOS, NEUT, RBCC, and RDW are not associated with the occurrence of glaucoma. This finding also supports previous observational studies associating immune components with glaucoma, thus provide guidance on the predication and prevention for glaucoma. [ABSTRACT FROM AUTHOR]

Preeclampsia is a pregnancy-related multisystem disorder characterized by altered trophoblast invasion, oxidative stress, exacerbation of systemic inflammatory response, and endothelial damage. The pathogenesis includes hypertension and mild-to-severe microangiopathy in the kidney, liver, placenta, and brain. The main mechanisms involved in its pathogenesis have been proposed to limit trophoblast invasion and increase the release of extracellular vesicles from the syncytiotrophoblast into the maternal circulation, exacerbating the systemic inflammatory response. The placenta expresses glycans as part of its development and maternal immune tolerance during gestation. The expression profile of glycans at the maternal-fetal interface may play a fundamental role in physiological pregnancy changes and disorders such as preeclampsia. It is unclear whether glycans and their lectin-like receptors are involved in the mechanisms of maternal-fetal recognition by immune cells during pregnancy homeostasis. The expression profile of glycans appears to be altered in hypertensive disorders of pregnancy, which could lead to alterations in the placental microenvironment and vascular endothelium in pregnancy conditions such as preeclampsia. Glycans with immunomodulatory properties at the maternal-fetal interface are altered in early-onset severe preeclampsia, implying that innate immune system components, such as NK cells, exacerbate the systemic inflammatory response observed in preeclampsia. In this article, we discuss the evidence for the role of glycans in gestational physiology and the perspective of glycobiology on the pathophysiology of hypertensive disorders in gestation. [ABSTRACT FROM AUTHOR]

Importance: Glaucoma is the second leading cause of blindness in the world. The causal direction and magnitude of the association between blood cell traits and glaucoma is uncertain because of the susceptibility of observational studies to confounding and reverse causation. Objective: To explore whether there is a causal relationship of blood cell traits including white blood cell (WBC) count (WBCC) and its subtypes [basophil cell count (BASO), monocyte cell count (MONO), lymphocyte cell count (LYMPH), eosinophil cell count (EOS), neutrophil cell count (NEUT)], red blood cell (RBC) count (RBCC), red blood distribution width (RDW), platelet count (PLT), and plateletcrit (PCT) on glaucoma risk. Methods: A two-sample Mendelian randomization (MR) analysis was conducted. Genome-wide significant single nucleotide polymorphisms (SNPs) from published genome-wide association studies (GWAS) on human blood cell traits were utilized as exposure instruments and the dataset for outcome was from the GWAS summary data of glaucoma. In the univariable MR analysis, we examined the association between genetic evidence of blood cell traits and glaucoma. To further investigate the potential causal mechanisms underlying the observed association, we performed multivariable MR analysis with three models, taking into account the mediator effect of inflammation and oxidative stress. According to Bonferroni-corrected for the 10 exposures in 3 methods, the MR study yielded a statistically significant p-value of 0.0017. Results: Genetically BASO, PCT, LYMPH, and PLT were potentially positively associated with glaucoma in the European ancestry [BASO: Odds ratio (OR) = 1.00122, 95% confidence interval (CI), 1.00003-1.00242, p = 0.045; PCT: OR = 1.00078, 95% CI, 1.00012-1.00143, p = 0.019; LYMPH: OR = 1.00076, 95% CI, 1.00002-1.00151, p = 0.045; PLT: OR = 1.00065, 95% CI, 1.00006-1.00123, p = 0.030], There was insufficient evidence to support a causal association of MONO, NEUT, EOS, WBCC, RBCC and RDW (MONO: OR = 1.00050, p = 0.098; NEUT: OR = 1.00028, p = 0.524; EOS: OR = 1.00020, p = 0.562; WBCC: OR = 1.00008, p = 0.830; RBCC: OR = 0.99996, p = 0.920; RDW: OR = 0.99987, p = 0.734) with glaucoma. The multivariable MR with model 1, 2, and 3 demonstrated that BASO, PCT, LYMPH, and PLT were still potentially genetically associated with the risk of glaucoma. Conclusion: Our study reveals a genetic predisposition to higher LYMPH, BASO, PLT, and PCT are associated with a higher risk of glaucoma, whereas WBCC, MONO, EOS, NEUT, RBCC, and RDW are not associated with the occurrence of glaucoma. This finding also supports previous observational studies associating immune components with glaucoma, thus provide guidance on the predication and prevention for glaucoma. [ABSTRACT FROM AUTHOR]

Thrombosis is a frequent cause of cardiovascular mortality and hospitalization. Current antithrombotic strategies, however, target both thrombosis and physiological hemostasis and thereby increase bleeding risk. In recent years the pathophysiological understanding of thrombus formation has significantly advanced and inflammation has become a crucial element. Neutrophils as most frequent immune cells in the blood and their released mediators play a key role herein. Neutrophil-derived cathelicidin next to its strong antimicrobial properties has also shown to modulates thrombosis and thus presents a potential therapeutic target. In this article we review direct and indirect (immune- and endothelial cell-mediated) effects of cathelicidin on platelets and the coagulation system. Further we discuss its implications for large vessel thrombosis and consecutive thromboinflammation as well as immunothrombosis in sepsis and COVID-19 and give an outlook for potential therapeutic prospects. [ABSTRACT FROM AUTHOR]

Iron oxide nanoparticles (IONPs) are widely used in diagnostic and therapeutic settings. Upon systemic administration, however, they are rapidly recognized by components of innate immunity, which limit their therapeutic capacity and can potentially lead to adverse side effects. IONPs were previously found to induce the inflammatory response in human whole blood, including activation of the complement system and increased secretion of cytokines. Here, we investigated the thromboinflammatory response of 10-30 nm IONPs in lepirudin anticoagulated whole blood in interplay with endothelial cells and evaluated the therapeutic effect of applying complement inhibitors to limit adverse effects related to thromboinflammation. We found that IONPs induced complement activation, primarily at the C3-level, in whole blood incubated for up to four hours at 37°C with and without human microvascular endothelial cells. Furthermore, IONPs mediated a strong thromboinflammatory response, as seen by the significantly increased release of 21 of the 27 analyzed cytokines (p<0.05). IONPs also significantly increased cell-activation markers of endothelial cells [ICAM-1 (p<0.0001), P/E-selectin (p<0.05)], monocytes, and granulocytes [CD11b (p<0.001)], and platelets [CD62P (p<0.05), CD63 (p<0.05), NAP-2 (p<0.01), PF4 (p<0.05)], and showed cytotoxic effects, as seen by increased LDH (p<0.001) and heme (p<0.0001) levels. We found that inflammation and endothelial cell activation were partly complement-dependent and inhibition of complement at the level of C3 by compstatin Cp40 significantly attenuated expression of ICAM-1 (p<0.01) and selectins (p<0.05). We show that complement activation plays an important role in the IONPs-induced thromboinflammatory response and that complement inhibition is promising in improving IONPs biocompatibility. [ABSTRACT FROM AUTHOR]

Non-classical HLA restricted T cell subsets such as γδ T and NK-T cells are showing promises for immune-based therapy of hematological malignancies. Mucosal-Associated Invariant T cells (MAIT) belong to this family of innate-like T cell subsets and are the focus of many studies on infectious diseases, owing to their unusual recognition of bacterial/fungal metabolites. Their ability to produce type 1 cytokines (IFNγ, TNFα) as well as cytotoxic effector molecules endows them with potential anti-tumor functions. However, their contribution to tumor surveillance in solid cancers is unclear, and only few studies have specifically focused on MAIT cells in blood cancers. In this review, we wish to recapitulate our current knowledge on MAIT cells biology in hematological neoplasms, at diagnosis and/or during treatment, as well as tentative approaches to target them as therapeutic tools. We also wish to take this opportunity to briefly elaborate on what we think are important question to address in this field, as well as potential limitations to overcome in order to make MAIT cells the basis of future, novel therapies for hematological cancers. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic sleeve gastrectomy (LSG) is a sustainable technique that effectively treats morbid obesity. However, the molecular mechanisms underlying the improvement of metabolic health following this process warrants more investigation. This study investigates LSG-related molecules and uses bulk RNA-sequencing high-throughput analysis to unravel their regulatory mechanisms. Methods: Peripheral blood mononuclear cells (PBMC) were collected from ten obese patients with BMI = 32.5 kg/m2 in the Department of General Surgery of Kunming First People's Hospital. After LSG, patients were followed up for one month, and blood samples were retaken. Blood samples from ten patients before and after LSG and bulk RNA-Seq data were analyzed in this study. LSG-associated gene expression was detected by weighted gene coexpression network analysis (WGCNA) and differential analysis. Subsequently, essential signature genes were identified using logistic least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and single-sample gene set enrichment analysis (ssGSEA) were utilized to reveal the potential functions of the target genes. Furthermore, the Pearson correlation of signature genes with leptin and lipocalin was also explored. Finally, we constructed a robust endogenous RNA (ceRNA) network based on miRWalk and starBase databases. Results: We identified 18 overlapping genes from 91 hub genes, and 165 differentially expressed mRNAs (DE-mRNA), which were revealed to be significantly associated with immune cells, immune response, inflammatory response, lipid storage, and localization upon functional enrichment analysis. Three signature genes, IRF1, NFKBIA, and YRDC, were identified from the 18 overlapping genes by LASSO and SVM-REF algorithms. The logistic regression model based on the three signature genes highlighted how robustly they discriminated between samples. ssGSEA indicated these genes to be involved in lipid metabolism and degradation pathways. Moreover, leptin levels were significantly reduced in patients undergoing LSG, and NFKBIA significantly negatively correlated with leptin. Finally, we identified how the long noncoding RNA (lncRNA) ATP2B1-AS1 regulated the expression of the signature genes by competitively binding to six microRNAs (miRNAs), which were hsamiR-6509-5p, hsa-miR-330-5P, hsa-miR-154-5P, hsa-miR-145-5P, hsamiR4726-5P and hsa-miR-134-5P. Conclusion: This study identified three critical regulatory genes significantly differentiated between patients before and after LSG treatment and highlighted their potentially crucial role after bariatric surgery. This provides novel insights to increase our understanding of the underlying mechanisms of weight loss and associated metabolic improvement after bariatric surgery. [ABSTRACT FROM AUTHOR]

Currently, the graft-versus-host disease (GVHD) prophylaxis consists of an immunosuppressive therapy mainly based on antithymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). GVHD remains a major complication and limitation to successful allogeneic haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We modified the ATG-based GVHD prophylaxis with the addition of basiliximab in the setting of haplo-HSCT and attempted to explore the appropriate dosages. We conducted a retrospective analysis of 239 patients with intermediate- or high-risk hematologic malignancies who received haplo-HSCT with unmanipulated peripheral blood stem cells combined or not with bone marrow. All patients received the same GVHD prophylaxis consisting of the combination of methotrexate, cyclosporine or tacrolimus, mycofenolatemofetil, and basiliximab with different doses of ATG (5-9mg/kg). With a median time of 11 days (range, 7-40 days), the rate of neutrophil engraftment was 96.65%. The 100-day cumulative incidences (CIs) of grade II-IV and III-IV aGVHD were 15.8 ± 2.5% and 5.0 ± 1.5%, while the 2-year CIs of total cGVHD and extensive cGVHD were 9.8 ± 2.2% and 4.1 ± 1.5%, respectively. The 3-year CIs of treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) were 14.6 ± 2.6%, 28.1 ± 3.4%, 60.9 ± 3.4%, 57.3 ± 3.4%, respectively. Furthermore, the impact of the reduction of the ATG dose to 6 mg/kg or less in combination with basiliximab on GVHD prevention and transplant outcomes among patients was analyzed. Compared to higher dose of ATG(>6mg/kg), lower dose of ATG (≤6mg/kg) was associated with a significant reduced risk of CMV viremia (52.38% vs 79.35%, P<0.001), while the incidences of aGVHD and cGVHD were similar between the two dose levels. No significant effect was found with regard to the risk of relapse, TRM, and OS. ATG combined with basiliximab could prevent GVHD efficiently and safely. The optimal scheme of using this combined regimen of ATG and basiliximab is that administration of lower dose ATG (≤6mg/kg), which seems to be more appropriate for balancing infection control and GVHD prophylaxis. [ABSTRACT FROM AUTHOR]

Intracellular calcium signaling regulates diverse physiological and pathological processes. In solid tumors, changes to calcium channels and effectors via mutations or changes in expression affect all cancer hallmarks. Such changes often disrupt transport of calcium ions (Ca2+) in the endoplasmic reticulum (ER) or mitochondria, impacting apoptosis. Evidence rapidly accumulates that this is similar in blood cancer. Principles of intracellular Ca2+ signaling are outlined in the introduction. We describe different Ca2+-toolkit components and summarize the unique relationship between extracellular Ca2+ in the endosteal niche and hematopoietic stem cells. The foundational data on Ca2+ homeostasis in red blood cells is discussed, with the demonstration of changes in red blood cell disorders. This leads to the role of Ca2+ in neoplastic erythropoiesis. Then we expand onto the neoplastic impact of deregulated plasma membrane Ca2+ channels, ER Ca2+ channels, Ca2+ pumps and exchangers, as well as Ca2+ sensor and effector proteins across all types of hematologic neoplasms. This includes an overview of genetic variants in the Ca2+-toolkit encoding genes in lymphoid and myeloid cancers as recorded in publically available cancer databases. The data we compiled demonstrate that multiple Ca2+ homeostatic mechanisms and Ca2+ responsive pathways are altered in hematologic cancers. Some of these alterations may have genetic basis but this requires further investigation. Most changes in the Ca2+-toolkit do not appear to define/associate with specific disease entities but may influence disease grade, prognosis, treatment response, and certain complications. Further elucidation of the underlying mechanisms may lead to novel treatments, with the aim to tailor drugs to different patterns of deregulation. To our knowledge this is the first review of its type in the published literature. We hope that the evidence we compiled increases awareness of the calcium signaling deregulation in hematologic neoplasms and triggers more clinical studies to help advance this field. [ABSTRACT FROM AUTHOR]

Purpose: It has previously been reported that repeated exposure to hypoxia increases spleen size and haemoglobin (HGB) level and recent reports on the effect apnoea has on spleen size and haematological parameters are contradictory. Therefore, this study aims to evaluate the effect apnoea training has on spleen size and haematological parameters. Methods: The breath-holding (BH) group was comprised of 12 local studentathletes with no BH exercise experience who performed BH jogging and BH jumping rope dynamic apnoea protocols, five times weekly for 8 weeks. The BH event duration was progressively increased as the apnoea tolerance of the athletes improved (20 to 35 s). The same training task was performed by the control group (n = 10) without BH. Spleen sizes were measured with an ultrasound system and a complete blood cell analysis was performed on the median cubital venous blood. Results: Spleen volume in the BH group increased from 109 ± 13ml to 136 ± 13 ml (p < 0.001), and bulky platelets decreased from 70.50 ± 5.83 to 65.17 ± 5.87 (p = 0.034), but no changes were recorded for erythrocytes (p = 0.914), HGB (p = 0.637), PLTs (p = 0.346) and WBC (p = 0.532). No changes were recorded for the control group regarding spleen size or haematological parameters. Conclusion: Eight weeks of dry dynamic apnoea training increased spleen size and decreased the number of circulating bulky platelets in the athletes who were assessed in this study. However, the baseline RBC counts and HGB levels of the athletes were not altered by the training programme. [ABSTRACT FROM AUTHOR]

Bone development have been shown to play an important role in regulating hematopoiesis as one major component of bone marrow microenvironment. Recent studies support the notion that there is an intricate relationship between hematopoiesis and bone homeostasis, however, little is known about the alterations in the hematopoietic lineages in pathologic conditions. Using various osteoporotic mouse models, we show here that bone microarchitecture abnormalities alter parameters of peripheral blood cells. The level of white blood cells is dynamics and negatively correlated with bone mineral density during the progression of osteoporosis. Furthermore, our clinical data confirm that osteoporosis is associated with abnormal circulating blood cell counts. These results demonstrated a causal link that osteoporosis is accompanied by the altered circulating blood cells, supporting the idea of a close interplay between hematopoiesis and bone homeostasis. Our study would propose that routine complete blood count might be applied as a potential diagnostic and putative marker for osteoporosis. [ABSTRACT FROM AUTHOR]

Regulatory B cells have important roles in inflammation and autoimmune diseases. A newly discovered subpopulation of B cells with a CD19hiFcγRIIbhi phenotype inhibits the proliferation of CD4+T cells by secreting interleukin (IL)-10. The expansion of CD19hiFcγRIIbhi B cells in mouse spleen can be induced by lipopolysaccharide (LPS) or CpG oligodeoxynucleotide stimulation. However, the mechanism of CD19hiFcγRIIbhi B cell expansion and its role in inflammatory diseases are unclear. Here, we report that, under inflammatory conditions, the proliferation and immunosuppressive function of CD19hiFcγRIIbhi B cells were decreased in high mobility group box1 (HMGB1) C106A mutant mice, compared with wild-type mice. The HMGB1 (C106A) mutation in B cells reduced STAT3 phosphorylation, restricting the expansion and suppressive function of CD19hiFcγRIIbhi B cells. Compared with CD19hiFcγRIIbhi B cells from wild-type mice, CD19hiFcγRIIbhi B cells from Hmgb1(C106A) mice significantly reduced the survival of mice with sepsis. Recombinant HMGB1 promoted the expansion of IL-10-producing CD19hiFcγRIIbhi B cells among LPS-activated B cells in vitro. Furthermore, the percentage of CD19hiFcyRIIbhi regulatory B cells in the peripheral blood was increased in patients with sepsis, compared with healthy controls. These findings implicate the role of HMGB1 in the expansion and immunosuppressive function of CD19hiFcγRIIbhi B cells. [ABSTRACT FROM AUTHOR]

Objective: To observe the early changes in peripheral blood cytokine levels after treatment of metastatic hepatic carcinoma (MHC) with CalliSpheres microspheres drug-eluting beads (DEB) transcatheter arterial chemoembolization (CSM-TACE). Methods: Twenty-eight patients with refractory MHC who underwent CSM-TACE were selected prospectively, and 5mL of peripheral blood was collected before CSM-TACE and on the 2nd and 5th day after CSM-TACE. Flow cytometry was used to detect immunological indicators. The early changes in levels of peripheral blood cell inflammatory factors Th1 (interleukin 2 (IL-2), tumor necrosis factor-a (TNF-a), interferon (IFN-r)), Th2 (IL-4, IL-6, IL-10), and Th17 (IL-17A) were observed after CSM-TACE, as well as the ratio of CD4+/CD8+. Results: All the 28 patients underwent CSM-TACE successfully. CT at 4 days after CSM-TACE showed clear outline low-density changes in liver tumors, and honeycomb necrosis was observed in the tumors in some cases. After CSM-TACE, the IL-6 and IL-10 levels were increased and then decreased again. After CSM-TACE, IL-2 showed a trend of transient increase and then decreased again, and the TNF-a level decreased temporarily, and then decreased. After CSM-TACE, the IFN-r level showed a continuous and slowly increasing trend. The IL-17 level showed a continuous downward trend, and the CD4+/CD8+ ratio showed a gradual and continuous upward trend, and there was a negative correlation between them. Conclusions: There are complex dynamic changes in TH1/Th2 in the early stage of CSM-TACE, and the acute inflammatory response and the enhancement of the body's immune anti-tumor response coexist. [ABSTRACT FROM AUTHOR]

Teneurin C-terminal associated peptide (TCAP) is an ancient bioactive peptide that is highly conserved in metazoans. TCAP administration reduces cellular and behavioral stress in vertebrate and urochordate models. There is little information for invertebrates regarding the existence or function of a TCAP. This study used the Sydney rock oyster (SRO) as a molluscan model to characterize an invertebrate TCAP, from molecular gene analysis to its physiological effects associated with hemocyte phagocytosis. We report a single teneurin gene (and 4 teneurin splice variants), which encodes a precursor with TCAP that shares a vertebrate-like motif, and is similar to that of other molluscan classes (gastropod, cephalopod), arthropods and echinoderms. TCAP was identified in all SRO tissues using western blotting at 1-2 different molecular weights (~22 kDa and ~37kDa), supporting precursor cleavage variation. In SRO hemolymph, TCAP was spatially localized to the cytosol of hemocytes, and with particularly high density immunoreactivity in granules. Based on 'pull-down' assays, the SRO TCAP binds to GAPDH, suggesting that TCAP may protect cells from apoptosis under oxidative stress. Compared to sham injection, the intramuscular administration of TCAP (5 pmol) into oysters modulated their immune system by significantly reducing hemocyte phagocytosis under stress conditions (low salinity and high temperature). TCAP administration also significantly reduced hemocyte reactive oxygen species production at ambient conditions and after 48 h stress, compared to sham injection. Transcriptomic hemocyte analysis of stressed oysters administered with TCAP demonstrated significant changes in expression of genes associated with key metabolic, protective and immune functions. In summary, this study established a role for TCAP in oysters through modulation of physiological and molecular functions associated with energy conservation, stress and cellular defense. [ABSTRACT FROM AUTHOR]

β3-adrenergic receptor (β3-AR) is the last β-adrenoceptor subtype identified. β3-AR is widely expressed and regulates numerous physiological processes, and it is also a potential target for the treatment of many diseases, including cancers. For some types of cancers, bone marrow transplant (BMT) represents a valid therapeutic support, especially in the case of the necessity of high-dose chemotherapy and radiotherapy. For a successful BMT, it is necessary that a donor's hematopoietic stem cells (HSCs) correctly reach the staminal niche in the recipient's bone marrow (BM) and contribute to restore normal hematopoiesis in order to rapidly repopulate BM and provide all the healthy blood cells of which the patient needs. Generally, it takes a long time. Control and accelerate homing and engraftment of HSCs could represent a helpful approach to avoid the complications and undesirable effects of BMT. The evidence that the β-adrenergic system has a role in the BM can be found in different studies, and this leads us to hypothesize that studying this field could be interesting to meliorate the most critical aspects of a BMT. Here, we collected the data present in literature about the role of β3-AR in the BM with the purpose of discovering a possible utility of β3-AR modulation in regulating HSC trafficking and hematopoiesis. [ABSTRACT FROM AUTHOR]

Parasitoids are widespread in natural ecosystems and normally equipped with diverse viral factors to defeat host immune responses. On the other hand, parasitoids can enhance the antibacterial abilities and improve the hypoimmunity traits of parasitized hosts that may encounter pathogenic infections. These adaptive strategies guarantee the survival of parasitoid offspring, yet their underlying mechanisms are poorly understood. Here, we focused on Cotesia vestalis , an endoparasitoid of the diamondback moth Plutella xylostella , and found that C. vestalis parasitization decreases the number of host hemocytes, leading to disruption of the encapsulation reaction. We further found that one bracovirus C-type lectin gene, CvBV_28-1 , is highly expressed in the hemocytes of parasitized hosts and participates in suppressing the proliferation rate of host hemocytes, which in turn reduces their population and represses the process of encapsulation. Moreover, CvBV_28-1 presents a classical bacterial clearance ability via the agglutination response in a Ca2+-dependent manner in response to gram-positive bacteria. Our study provides insights into the innovative strategy of a parasitoid-derived viral gene that has dual functions to manipulate host immunity for a successful parasitism. [ABSTRACT FROM AUTHOR]

The bone marrow (BM) niche is the spatial structure within the intra-trabecular spaces of spongious bones and of the cavity of long bones where adult haematopoietic stem cells (HSCs) maintain their undifferentiated and cellular self-renewal state through the intervention of vascular and nervous networks, metabolic pathways, transcriptional and epigenetic regulators, and humoral signals. Within the niche, HSCs interact with various cell types such as osteoblasts, endothelial cells, macrophages, and mesenchymal stromal cells (MSCs), which maintain HSCs in a quiescent state or sustain their proliferation, differentiation, and trafficking, depending on body needs. In physiological conditions, the BM niche permits the daily production of all the blood and immune cells and their admittance/ingress/progression into the bloodstream. However, disruption of this delicate microenvironment promotes the initiation and progression of malignancies such as those included in the spectrum of myeloid neoplasms, also favouring resistance to pharmacological therapies. Alterations in the MSC population and in the crosstalk with HSCs owing to tumour-derived factors contribute to the formation of a malignant niche. On the other hand, cells of the BM microenvironment cooperate in creating a unique milieu favouring metastasization of distant tumours into the bone. In this framework, the pro-tumorigenic role of MSCs is well-documented, and few evidence suggest also an anti-tumorigenic effect. Here we will review recent advances regarding the BM niche composition and functionality in normal and in malignant conditions, as well as the therapeutic implications of the interplay between its diverse cellular components and malignant cells. [ABSTRACT FROM AUTHOR]

Glycosylation of CD45RB (RB+) has recently been identified to mark antigen-experienced B cells, independent of their CD27 expression. By using a novel combination of markers including CD45RB glycosylation, CD27 and IgM/IgD isotype expression we segregated human peripheral blood B cell subsets and investigated their IGHV repertoire and in vitro functionality. We observed distinct maturation stages for CD27-RB+ cells, defined by differential expression of non-switched Ig isotypes. CD27-RB+ cells, which only express IgM, were more matured in terms of Ig gene mutation levels and function as compared to CD27-RB+ cells that express both IgM and IgD or cells that were CD27-RB-. Moreover, CD27-RB+IgM+ cells already showed remarkable rigidity in IgM isotype commitment, different from CD27-RB+IgMD+ and CD27-RB- cells that still demonstrated great plasticity in B cell fate decision. Thus, glycosylation of CD45RB is indicative for antigen-primed B cells, which are, dependent on the Ig isotype, functionally distinct. [ABSTRACT FROM AUTHOR]

The rate of complete remission of acute promyelocytic leukemia (APL) is currently over 90% because of the use of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). However, hemorrhagic mortality has emerged as the most significant barrier to APL-induced remission. Neutrophils extracellular traps (NETs/ETs) cause vascular leakage by damaging the integrity of endothelial cells. We have previously demonstrated that APL cells treated with ATRA/ATO undergo a cell death process, releasing extracellular chromatin, termed ETosis/NETosis. However, the mechanism underlying the involvement of ETs in endothelial injury in APL remain largely unknown. Here, we analysed the ability of mature and immature neutrophils to release ETs, and their interaction with platelets (PLTs) in APL. Importantly, the effect of ETs on vascular endothelium in APL was discussed. Our results showed that the ability of immature neutrophils to release ETs was impaired in APL, whereas mature neutrophils produced ETs, which were associated with activated PLTs. Moreover, ATRA+ATO induced immature neutrophil differentiation, as well as increased the release of ETs from mature neutrophils. The excessive ETs damaged endothelial cells, causing blood cell leakage. Removing ETs using DNase 1 alleviated endothelial damage and improved blood cells leakage. Our results indicate that vascular endothelial injury is at least partially associated with ETs in APL, and that targeting ETs production may be an effective approach for relieving vascular leakage and reducing the burden of bleeding in APL. [ABSTRACT FROM AUTHOR]

The genetic bases and disparate responses to radiotherapy are poorly understood, especially for cardiotoxicity resulting from treatment of thoracic tumors. Preclinical animal models such as the Dahl salt-sensitive (SS) rat can serve as a surrogate model for salt-sensitive low renin hypertension, common to African Americans, where aldosterone contributes to hypertension-related alterations of peripheral vascular and renal vascular function. Brown Norway (BN) rats, in comparison, are a normotensive control group, while consomic SSBN6 with substitution of rat chromosome 6 (homologous to human chromosome 14) on an SS background manifests cardioprotection and mitochondrial preservation to SS rats after injury. In this study, 2 groups from each of the 3 rat strains had their hearts irradiated (8 Gy X 5 fractions). One irradiated group was treated with the ACE-inhibitor lisinopril, and a separate group in each strain served as nonirradiated controls. Radiation reduced cardiac end diastolic volume by 9-11% and increased thickness of the interventricular septum (11-16%) and left ventricular posterior wall (14-15%) in all 3 strains (5-10 rats/group) after 120 days. Lisinopril mitigated the increase in posterior wall thickness. Mitochondrial function was measured by the Seahorse Cell Mitochondrial Stress test in peripheral blood mononuclear cells (PBMC) at 90 days. Radiation did not alter mitochondrial respiration in PBMC from BN or SSBN6. However, maximal mitochondrial respiration and spare capacity were reduced by radiation in PBMC from SS rats (p=0.016 and 0.002 respectively, 9-10 rats/group) and this effect was mitigated by lisinopril (p=0.04 and 0.023 respectively, 9-10 rats/group). Taken together, these results indicate injury to the heart by radiation in all 3 strains of rats, although the SS rats had greater susceptibility for mitochondrial dysfunction. Lisinopril mitigated injury independent of genetic background. [ABSTRACT FROM AUTHOR]

Protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium -infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral 'TRM-like' cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM−like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach. [ABSTRACT FROM AUTHOR]

JAK/STAT signaling regulates central biological functions such as development, cell differentiation and immune responses. In Drosophila , misregulated JAK/STAT signaling in blood cells (hemocytes) induces their aberrant activation. Using mass spectrometry to analyze proteins associated with a negative regulator of the JAK/STAT pathway, and by performing a genome-wide RNAi screen, we identified several components of the proteasome complex as negative regulators of JAK/STAT signaling in Drosophila. A selected proteasome component, Prosα6 , was studied further. In S2 cells, Prosα6 silencing decreased the amount of the known negative regulator of the pathway, ET, leading to enhanced expression of a JAK/STAT pathway reporter gene. Silencing of Prosα6 in vivo resulted in activation of the JAK/STAT pathway, leading to the formation of lamellocytes, a specific hemocyte type indicative of hemocyte activation. This hemocyte phenotype could be partially rescued by simultaneous knockdown of either the Drosophila STAT transcription factor, or MAPKK in the JNK-pathway. Our results suggest a role for the proteasome complex components in the JAK/STAT pathway in Drosophila blood cells both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Familial focal epilepsy with variable foci is an autosomal dominant disorder characterized by partial epilepsy with variable foci. In this study, we report a six-generation with segregation of the mutation present in four generations Chinese family presenting with focal epilepsy with variable foci. Whole exome sequencing confirms a novel pathogenic mutation in the NPRL3 gene (c316C>T; p. Q106*). PCR, Western blotting, and immunohistochemistry were conducted to analyze the gene transcription, protein expression, and subcellular localization of NPRL3 and related signaling molecules in peripheral blood cells from family members. As compared with healthy family members, both mRNA level and protein expression of NPRL3 are decreased in peripheral blood cells of the mutation carrier. In addition, the expression of downstream molecular Phospho-p70 S6 kinase (P-s6k) are increased consequently. Our findings expand the genotypic and phenotypic spectrum of the NPRL3-associated epilepsy and reveal the mechanisms of mTOR pathway signaling and GATOR1 pathogenesis in focal epilepsies, providing exciting potential for future diagnostic and therapeutic interventions. However, further in vitro and animal experiments are still needed to evaluate the role of NPRL3 loss-of-function mutation in epileptogensis. [ABSTRACT FROM AUTHOR]