The Reconstitution of T-cells after Allogeneic Hematopoietic Stem Cell Transplant in a Pediatric Patient with Congenital Amegakaryocytic Thrombocytopenia (CAMT).

BACKGROUND: Congenital amegakaryocytic thrombocytopenia (CAMT) is a bone marrow failure syndrome with autosomal recessive inheritance characterized by the lack of megakaryocytes and thrombocytopenia. The cause of the disease is a mutation in the c-Mpl gene, which encodes the thrombopoietin (TPO) receptor. The main treatment for this genetic disorder is an allogeneic hematopoietic stem cell transplant (allo-HSCT). However, transplant-related mortality, development of acute and chronic graft-versushost disease (GvHD), and susceptibility to opportunistic infections are major barriers to transplantation. Delay in the reconstitution of T cells and imbalance in the regeneration of distinct functional CD4 and CD8 T-cell subsets mainly affect post-transplant complications. We report a case of CAMT, who developed acute GvHD but had no signs and symptoms of chronic GvHD following allo-HSCT. CASE PRESENTATION: At the age of four, she presented with petechiae and purpura. In laboratory investigations, pancytopenia without organomegaly, and cellularity less than 5% in bone marrow biopsy, were observed. A primary diagnosis of idiopathic aplastic anemia was made, and she was treated with prednisolone, cyclosporine, and anti-thymocyte globulin (ATG), which did not respond. Genetic analysis revealed the mutation c.1481T>G (p. L494W) in exon 10 of the c-Mpl gene, and the diagnosis of CAMT was confirmed. The patient underwent allo-HSCT from a healthy sibling donor. Alloimmunization reactions and immune disorders were present due to long-term treatment with immunosuppressive medications and repeated blood and platelet transfusions. Hence, the regeneration of T-lymphocytes after allo-HSCT was evaluated. CONCLUSION: Successful treatment of acute GvHD prevented advancing the condition to chronic GvHD, and this was accompanied by delayed T-cell reconstitution through an increase in Treg:Tcons ratio.

Artificial Intelligence and Acute Appendicitis: A Systematic Review of Diagnostic and Prognostic Models.

BACKGROUND: To assess the efficacy of artificial intelligence (AI) models in diagnosing and prognosticating acute appendicitis (AA) in adult patients compared to traditional methods. AA is a common cause of emergency department visits and abdominal surgeries. It is typically diagnosed through clinical assessments, laboratory tests, and imaging studies. However, traditional diagnostic methods can be time-consuming and inaccurate. Machine learning models have shown promise in improving diagnostic accuracy and predicting outcomes. MAIN BODY: A systematic review following the PRISMA guidelines was conducted, searching PubMed, Embase, Scopus, and Web of Science databases. Studies were evaluated for risk of bias using the Prediction Model Risk of Bias Assessment Tool. Data points extracted included model type, input features, validation strategies, and key performance metrics. RESULTS: In total, 29 studies were analyzed, out of which 21 focused on diagnosis, seven on prognosis, and one on both. Artificial neural networks (ANNs) were the most commonly employed algorithm for diagnosis. Both ANN and logistic regression were also widely used for categorizing types of AA. ANNs showed high performance in most cases, with accuracy rates often exceeding 80% and AUC values peaking at 0.985. The models also demonstrated promising results in predicting postoperative outcomes such as sepsis risk and ICU admission. Risk of bias was identified in a majority of studies, with selection bias and lack of internal validation being the most common issues. CONCLUSION: AI algorithms demonstrate significant promise in diagnosing and prognosticating AA, often surpassing traditional methods and clinical scores such as the Alvarado scoring system in terms of speed and accuracy.

Exploring the pharmacological versatility of ficus carica: Modulating classical immunometabolism and beyond.

The burden of metabolic disorders is alarmingly increasing globally. On the other hand, sustainability is the key project of the 21st century. Natural products offer a coherent option for the complementary management of both these challenges. Ficus carica (FC), commonly known as the fig fruit, has an experimentally proven potency for the modulation of cell cycle, immunity, inflammation, metabolism, and oxidative stress. Here, we review the potential of FC-derived products (FCDP) in slowing down the progression of cancers, acute/chronic inflammation-related conditions, infections, metabolic disorders, toxicities, neurological and neuromuscular diseases, gastrointestinal disorders, vascular diseases, and skin-stressing conditions, as well as, in boosting normal healthy functions of the endocrine, immune, metabolic, and nervous systems. It reveals a variety of cellular and molecular targets for FCDP: cytokines (TNF-α, IL-1ß, IL-6, IL-10, IL-12, IL-18, IFN-γ), chemokines (CCL2), other inflammatory mediators (CRP, PGE2), immune receptors (TLR-2, TLR-4, FcεRI), oxidative stress-related markers (SOD, GSH, MDA, GPx, catalase, ROS, NO, protein carbonyls), kinases (MAPKs, hexokinase, G6Pase, FBPase, PEPCK, Akt, AMPK, GSK3, CDKs), other enzymes (COX-2, iNOS, MMPs, caspases), growth factors/receptors (VEGF, EGFR), hormones (DHEAS, prolactin, GnRH, FSH, LH, estradiol, DHT, insulin), cell death-related markers (Bcl-2, Bax, Bak, FasL, gasdermins, cytochrome C), glucose transporter protein (Glut4), and transcription factors (NF-κB, HNF-4α, Foxo, PGC-1α, PPAR-γ, C/EBP-α, CREB, NFATC1, STAT3). FCDP cause both activation and inhibition of AMPK, MAPK, and NF-κB signaling to confer condition-specific advantages. Such a broad-range activity might be attributed to different mechanisms of action of FCDP in modulating functions within the classical immunometabolic system, but also beyond.

Post-COVID-19 depression and serum interleukin 6 levels: A systematic review and meta-analysis of COVID-19 convalescents with and without depression.

OBJECTIVES: Depression is among the psychiatric sequelae of COVID-19, affecting more than 20% of the convalescents. Its underlying pathophysiology remains unclear. Interleukin 6 (IL-6), a pro-inflammatory cytokine, plays a critical role in the COVID-19-associated cytokine storm, has been implicated in depressive disorders, and may thus be involved in post-COVID-19 depression. METHODS: PubMed, Scopus, Embase, and Web of Science were systematically searched for relevant studies assessing peripheral IL-6 levels in convalescents who developed depression after COVID-19 vs. convalescents who did not. RESULTS: Five studies were included in our systematic review, and four entered the meta-analysis. The meta-analysis revealed that post-COVID people with de novo depression did not have statistically significant differences in IL-6 levels compared to those without depression (standardised mean difference (SMD) = 0.09, 95% confidence interval (CI) = -0.35, 0.54, p-value = 0.68). CONCLUSIONS: Although convalescents with depression did not have significantly higher IL-6 levels than convalescents without depression, the results should be interpreted considering the limited sample size and the low power of the included studies.

Diagnostic accuracy of intravoxel incoherent motion (IVIM) and dynamic contrast-enhanced (DCE) MRI to differentiate benign from malignant breast lesions: A systematic review and meta-analysis.

PURPOSE: Magnetic resonance imaging (MRI) can reduce the need for unnecessary invasive diagnostic tests by nearly half. In this meta-analysis, we investigated the diagnostic accuracy of intravoxel incoherent motion modeling (IVIM) and dynamic contrast-enhanced (DCE) MRI in differentiating benign from malignant breast lesions. METHOD: We systematically searched PubMed, EMBASE, and Scopus. We included English articles reporting diagnostic accuracy for both sequences in differentiating benign from malignant breast lesions. Articles were assessed by quality assessment of diagnostic accuracy studies-2 (QUADAS-2) questionnaire. We used a bivariate effects model for standardized mean difference (SMD) analysis and diagnostic test accuracy analysis. RESULTS: Ten studies with 537 patients and 707 (435 malignant and 272 benign) lesions were included. The D, f, Ktrans, and Kep mean values significantly differ between benign and malignant lesions. The pooled sensitivity (95 % confidence interval) and specificity were 86.2 % (77.9 %-91.7 %) and 70.3 % (56.5 %-81.1 %) for IVIM, and 93.8 % (85.3 %-97.5 %) and 68.1 % (52.7 %-80.4 %) for DCE, respectively. Combined IVIM and DCE depicted the highest area under the curve of 0.94, with a sensitivity and specificity of 91.8 % (82.8 %-96.3 %) and 87.6 % (73.8 %-94.7 %), respectively. CONCLUSIONS: Combined IVIM and DCE had the highest diagnostic accuracy, and multiparametric MRI may help reduce unnecessary benign breast biopsy.

Disturbance in the reconstitution of distinct T-cell subsets and the incidence of GvHD following allo-HSCT in pediatric patients with non-malignant hematological disorders.

BACKGROUND: The reconstitution of different T-cell subsets following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is critical for efficient pathogen protection and the prevention of graft-versus-host disease (GvHD). In particular, studies have highlighted the importance of balanced ratios of regulatory T-cells (Tregs) and distinct functionally T-cells in preventing acute and chronic GvHD. METHODS: We evaluated the regeneration of CD4 and CD8 T-cell subpopulations in nine pediatric patients with non-malignant disorders following allo-HSCT from a fully HLA-identical donor. RESULTS: CD4 and CD8 T-cells were higher 12 months after the transplant but still lower than in healthy controls and pre-transplant. However, we found after allo-HSCT, central memory and effector memory cell subsets were the predominant phenotypes in the CD4 and CD8 T-cell populations, respectively. In patients who had developed acute GvHD, there was an increase in the frequency of TEMRA (effector memory T cells that re-express CD45RA) cells within the CD4 T-cell population. Meanwhile, in patients with chronic GvHD, we observed a decrease in Th1 cells in CD4 T-cells and effector memory cells within the CD8 T-cell population. In addition, we found decreased TEMRA cell subsets in CD4 and CD8 T-cell populations in chronic GvHD. CONCLUSION: Our findings suggest a possible relationship between the influence of acute GvHD and its prevention on delayed CD4 T-cell reconstitution and, reciprocally, unbalanced regeneration of CD4 and CD8 T-cell subsets in the development of chronic GvHD.

Clinical efficacy and safety of bispecific antibodies for the treatment of solid tumors: a systematic review and meta-analysis.

INTRODUCTION: Immunotherapy is a promising and progressing treatment approach for cancer. Bispecific antibodies (BsAbs) are antibody constructs that can bind to two different epitopes. The dual-specificity of BsAbs improves their efficacy compared to monoclonal antibodies. AREAS COVERED: Although BsAbs have achieved excellent therapeutic effects in hematologic cancers, no systematic review with meta-analysis evaluated their efficacy in solid tumors. In the present systematic review and meta-analysis, we aimed to establish the clinical efficacy and safety of BsAbs in solid tumors. EXPERT OPINION: BsAbs are not associated with significantly better safety or efficacy outcomes than conventional therapies. BsAb was not associated with improvement in overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). However, BsAb increased the rate of stable disease (SD) significantly. Also, BsAb substantially increased the OS and PFS and resulted in a higher frequency of DCR for uveal melanoma. Furthermore, the safety analysis showed no obvious difference in the rate of any adverse events (AEs), grade ≥3 AEs, serious AEs, and AEs leading to treatment discontinuation in the intervention group compared to controls. Further high-quality randomized controlled trials on BsAbs in solid tumors are highly recommended.

Nanotechnology-based diagnostics and therapeutics in acute lymphoblastic leukemia: a systematic review of preclinical studies.

Background: Leukemia is a malignant disease that threatens human health and life. Nano-delivery systems improve drug solubility, bioavailability, and blood circulation time, and release drugs selectively at desired sites using targeting or sensing strategies. As drug carriers, they could improve therapeutic outcomes while reducing systemic toxicity. They have also shown promise in improving leukemia detection and diagnosis. The study aimed to assess the potential of nanotechnology-based diagnostics and therapeutics in preclinical human acute lymphoblastic leukemia (h-ALL). Methods: We performed a systematic search through April 2022. Articles written in English reporting the toxicity, efficacy, and safety of nanotechnology-based drugs (in the aspect of treatment) and specificity, limit of detection (LOD), or sensitivity (in the aspect of the detection field) in preclinical h-ALL were included. The study was performed according to PRISMA instructions. The methodological quality was assessed using the QualSyst tool. Results: A total of 63 original articles evaluating nanotechnology-based therapeutics and 35 original studies evaluating nanotechnology-based diagnostics were included in this review. As therapeutics in ALL, nanomaterials offer controlled release, targeting or sensing ligands, targeted gene therapy, photodynamic therapy and photothermic therapy, and reversal of multidrug-resistant ALL. A narrative synthesis of studies revealed that nanoparticles improve the ratio of efficacy to the toxicity of anti-leukemic drugs. They have also been developed as a vehicle for biomolecules (such as antibodies) that can help detect and monitor leukemic biomarkers. Therefore, nanomaterials can help with early diagnostics and personalized treatment of ALL. Conclusion: This review discussed nanotechnology-based preclinical strategies to achieve ALL diagnosis and therapy advancement. This involves modern drug delivery apparatuses and detection devices for prompt and targeted disease diagnostics. Nonetheless, we are yet in the experimental phase and investigational stage in the field of nanomedicine, with many features remained to be discovered as well as numerous problems to be solved.

T helper 17 and regulatory T-cell profile and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in pediatric patients with beta-thalassemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option for hereditary hemoglobin disorders, such as beta-thalassemia; However, this procedure is not without constraints, mainly engendering complications such as acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), and susceptibility to infections. The clinical outcomes of allo-HSCT are highly dependant on the quality and quantity of T-cell subsets reconstitution. Following the allo-HSCT of six pediatric patients afflicted with beta-thalassemia, their mononuclear cells were isolated, and then cultured with a combination of phorbol myristate acetate (PMA)/ionomycin and Brefeldin A. The content of CD4 T-cell subsets, including T helper 17 (Th17) cells and regulatory T cells (Tregs), were determined by specific conjugated-monoclonal antibodies three and six months post-HSCT. An increased frequency of total CD4 T-cells, Tregs and Th17 cells was observed at day 90 and 180 after allo-HSCT, albeit the numbers were still lower than that of our healthy controls. In patients who developed cGvHD, a lower Th17/Treg ratio was observed, owing it to a decreased proportion of Th17 cells. In conclusion, creating balance between Th17 and Treg subsets may prevent acute and chronic GvHD in patients after allo-HSCT.

Inosine, gut microbiota, and cancer immunometabolism.

This article briefly reviews cancer immunity and the role of gut microbiota in carcinogenesis, followed by an understanding of mechanisms by which inosine is involved in cancer immunometabolism. The immune system plays a paradoxical role in cancer treatment. Antitumor immunity depends on the T-cell priming against tumor antigens, whereas inflammatory mediators trigger the protumor signaling in the tumor microenvironment. Studies link the microbiome with metabolism and immunity-two main factors implicated in carcinogenesis. Gut microbiota has been shown to affect both antitumor immunity and protumor immune signaling. There is mounting evidence that the human microbiome can play a role in the immunotherapeutic effects, both response and resistance. Inosine-5'-monophosphate dehydrogenase (IMPDH) is a highly conservative enzyme widely expressed in mammals. Cell signaling pathways use molecular inosine, a crucial secondary metabolite in purine metabolism and a molecular messenger. Recent research has identified inosine as a critical regulator of immune checkpoint inhibition (ICI) therapeutic response in various tumor types. Some bacterial species were found to produce inosine or its metabolite hypoxanthine and induce T-helper 1 differentiation and effector functions via the inosine-A2AR-cAMP-PKA pathway upon ICI therapy. Also, inosine acts as a substitute carbon source for T-cell metabolism in glucose-restricted environments, i.e., the tumor microenvironment, assisting T-cell proliferation and differentiation while enhancing sensitivity to ICI, reinforcing the notion that inosine metabolism might contribute to antitumor immunity. Also, inosine is a potent agonist of the adenosine receptor, A2AR, and A2AR signaling can affect T-cell responses and antitumor immunity, making the inosine-A2AR pathway blockage a candidate for cancer treatment. Further research is required to investigate inosine as a cancer immunometabolism therapy.

BDNF and its signaling in cancer.

PURPOSE: Brain-derived neurotrophic factor (BDNF) belongs to the family of neurotrophic factors that can potentially increase cancer cell growth, survival, proliferation, anoikis, and migration by tyrosine kinase receptors TrkB and the p75NTR death receptor. The activation of BDNF/TrkB pathways leads to several downstream signaling pathways, including PI3K/Akt, Jak/STAT, PLCγ, Ras-Raf-MEK-ERK, NF-kB, and transactivation of EGFR. The current review aimed to provide an overview of the role of BDNF and its signaling in cancer. METHODS: We searched a major medical database, PubMed, to identify eligible studies for a narrative synthesis. RESULTS: Pathological examinations demonstrate BDNF overexpression in human cancer, notably involving the prostate, lung, breast, and underlying tissues, associated with a higher death rate and poor prognosis. Therefore, measurement of BDNF, either for identifying the disease or predicting response to therapy, can be helpful in cancer patients. Expression profiling studies have recognized the role of microRNAs (miR) in modulating BDNF/TrkB pathways, such as miR-101, miR-107, miR-134, miR-147, miR-191, miR-200a/c, miR-204, miR-206, miR-210, miR-214, miR-382, miR-496, miR-497, miR-744, and miR-10a-5p, providing a potential biological mechanism by which targeted therapies may correlate with decreased BDNF expression in cancers. Clinical studies investigating the use of agents targeting BDNF receptors and related signaling pathways and interfering with the related oncogenic effect, including Entrectinib, Larotrectinib, Cabozantinib, Repotrectinib, Lestaurtinib, and Selitrectinib, are in progress. CONCLUSION: The aberrant signaling of BDNF is implicated in various cancers. Well-designed clinical trials are needed to clarify the BDNF role in cancer progression and target it as a therapeutic method.

MicroRNA expression profiles of peripheral blood and mononuclear cells in myasthenia gravis: A systematic review.

BACKGROUND: Studies have described the role of microRNAs (miRNAs) in thymic function, along with directly observing the altered expression of miRNAs in thymuses of myasthenia gravis (MG) patients; so, miRNAs became a core component in the pathophysiology of MG. However, because the miRNA analysis results are contradictory, the identification of MG-related miRNAs is daunting. OBJECTIVE: We did a systematic review of studies analyzing the miRNA expression profile of peripheral blood and mononuclear cells for patients with MG. METHODS: We ran a database search in PubMed, Scopus, and Web of Science on August 17, 2021. Original articles that analyzed miRNA profiles in peripheral blood (serum, plasma, and whole blood) and peripheral blood mononuclear cells (PBMCs) for patients with MG in comparison with a non-MG or healthy control (HC) group were eligible. The quality of studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). RESULTS: 26 studies were included. The quality of studies was fair (median score, 5). Among 226 different miRNAs that were deregulated in at least one study (range, 1-87), ten miRNAs were significantly deregulated in three or more studies. Five miRNAs (50%) showed the same deregulation: miR-106b-3p and miR-21-5p were consistently upregulated, and miR-20b, miR-15b, and miR-16 were consistently downregulated. Also, there were five miRNAs that were mostly upregulated, miR-150-5p, miR-146a, miR-30e-5p, and miR-338-3p, or downregulated, miR-324-3p, across studies. CONCLUSION: These miRNAs contribute to different pathways, importantly neural apoptosis and autophagy, inflammation, T regulatory cell development, and T helper cell balance. Prior to being used for diagnostic and therapeutic purposes, it is required to pursue molecular mechanisms these consistently and mostly dysregulated miRNAs specifically use in the context of MG.

Elevated neopterin in tuberculosis and co-infection with HIV and the effect of treatment: A systematic review, meta-analysis, and meta-regression.

BACKGROUND: Neopterin (NEO) is a marker of immune stimulation. Increased NEO levels have been associated with autoimmune diseases, infections, and malignancies. Studies of NEO alterations in tuberculosis (TB) with or without HIV co-infection show inconsistent results. Moreover, challenges exist regarding TB diagnosis in people with HIV. METHODS: We did a systematic review and meta-analysis of studies comparing urinary, pleural, and blood NEO levels between patients with TB or HIV-TB co-infection as the case group and subjects without TB and HIV or subjects with HIV without TB as the control group, respectively. RESULTS: Blood NEO levels in patients with active TB were higher than healthy controls, with a large effect size of 1.99. Patients with TB had higher blood NEO levels before anti-tuberculosis therapy (ATT) than after ATT for months or when treatment ended with moderate effect sizes (1.13-1.46). meta-analysis of studies of patients with HIV-TB co-infection yielded similar results, with higher blood NEO levels in patients than controls that remained significant in subgroups of studies on pulmonary TB (PTB) patients and serum NEO and higher blood NEO levels in patients before than after ATT. CONCLUSION: Meta-analyses reveal alteration in NEO levels in different specimens, e.g., blood, urine, and pleural fluid, in patients with TB with or HIV-TB co-infection compared to the control groups. Future studies need to investigate the utility of NEO as a diagnostic/prognostic biomarker for TB. Also, cellular and molecular mechanisms linking NEO and TB remain to be addressed.

Venous thromboembolism in cancer and cancer immunotherapy.

Venous thromboembolism (VTE) is a clinical disease that includes deep vein thrombosis and pulmonary embolism. Amongst its underlying risk factors, cancer is of great importance. Stasis, endothelial injury, and hypercoagulability result in clot formation and VTE. Cancer can affect coagulability by favoring these three factors, resulting in VTE incidence. Immunotherapy is a novel therapeutic approach, targeting cancer by immune system enhancement. VTE is one of the most important adverse effects of immunotherapy, which complicates the administration of immunotherapy in cancer patients. The current review provides a brief overview of VTE epidemiology, pathophysiology, risk factors, biomarkers, the relationship of cancer and cancer immunotherapy to VTE incidence, and managing cancer-associated VTE.

Clinical safety and efficacy of bispecific antibody in the treatment of solid tumors: A protocol for a systematic review.

BACKGROUND: Cancers are among the most common causes of mortality and morbidity. Recently, bispecific antibodies (BsAbs) have been used for cancer treatment. The aim of this systematic review and meta-analysis will be to determine the safety and efficacy of BsAbs in the treatment of solid tumors. METHODS: We will search five electronic databases, PubMed, EMBASE, Scopus, Web of Science, and CENTRAL, in addition to Clinical-Trials.gov and metaRegister of controlled trials and backward and forward citation searching of included studies. Eligible studies will be controlled clinical trials evaluating safety and/or efficacy of BsAbs in adult patients with solid tumors. The primary outcomes will be the incidence of safety and efficacy measures. Title and/or abstract screening, full text reviewing, data collection, and quality assessment will be done by two reviewers. We will use The Cochrane Collaboration's risk of bias tool 2 (RoB2) to assess the quality of included studies. If I-square heterogeneity was greater than 40%, we will implement random effect model. Subgroup analysis and meta-regression will be undertaken if applicable. The metaprop command of STATA will be used to calculate frequency of AEs. Funnel plot, Egger's and Peter's tests will be utilized to evaluate publication bias in case of including at least ten studies. We will use sensitivity analysis to evaluate the effects of funding sources and continuity correction on effects size. CONCLUSIONS: The findings of the present study will provide information on safety and efficacy of BsAbs for physicians and researchers in the management of solid tumors. TRIAL REGISTRATION: Registration on PROSPERO CRD42021227879 Also, important protocol amendments will be stated on PROSPERO registration.

Vascular endothelial growth factor levels in tuberculosis: A systematic review and meta-analysis.

BACKGROUND: Changes in endothelial function are implicated in the spread of tuberculosis (TB). Studies suggest a role for the vascular endothelial growth factor (VEGF) in TB-related endothelial function changes. However, the findings of studies investigating the VGEF profile in TB are not consistent, and no formal systematic review and meta-analysis exists summarizing these studies. METHODS: We did a meta-analysis of studies assessing VEGF levels in patients with TB. A systematic search on June 25, 2021, was conducted for eligible studies that made VEGF measurements in an unstimulated sample, e.g., a blood fraction (plasma or serum), cerebrospinal fluid (CSF), pleural effusion (PE), or bronchoalveolar lavage fluid, and ascites or pericardial fluid for patients with TB and controls without TB. Also, studies that made simultaneous measurements of VEGF in blood and PE or CSF in the same patients with TB were included. Longitudinal studies that provided these data at baseline or compared pre-post anti-tuberculosis treatment (ATT) levels of VEGF were included. The primary outcome was the standardized mean difference (SMD) of VEGF levels between the comparison groups. RESULTS: 52 studies were included in the meta-analysis. There were 1787 patients with TB and 3352 control subjects of eight categories: 107 patients with transudative pleural effusion, 228 patients with congestive heart failure (CHF)/chronic renal failure (CRF), 261 patients with empyema and parapneumonic effusion (PPE), 241 patients with cirrhosis, 694 healthy controls (with latent TB infection or uninfected individuals), 20 patients with inactive tuberculous meningitis (TBM), 123 patients with non-TBM, and 1678 patients with malignancy. The main findings are as follows: (1) serum levels of VEGF are higher in patients with active TB compared with healthy controls without other respiratory diseases, including those with latent TB infection or uninfected individuals; (2) both serum and pleural levels of VEGF are increased in patients with TPE compared with patients with transudative, CHF/CRF, or cirrhotic pleural effusion; (3) ascitic/pericardial fluid, serum, and pleural levels of VEGF are decreased in patients with TB compared with patients with malignancy; (4) pleural levels of VEGF are lower in patients with TPE compared with those with empyema and PPE, whereas serum levels of VEGF are not different between these patients; (5) both CSF and serum levels of VEGF are increased in patients with active TBM compared with controls, including patients with inactive TBM or non-TBM subjects; (6) post-ATT levels of VEGF are increased compared with pre-ATT levels of VEGF; and (7) the mean age and male percentage of the TB group explained large and total amount of heterogeneity for the meta-analysis of blood and pleural VEGF levels compared with healthy controls and patients with PPE, respectively, whereas these moderators did not show any significant interaction with the effect size for other analyses. DISCUSSION: The important limitation of the study is that we could not address the high heterogeneity among studies. There might be unmeasured factors behind this heterogeneity that need to be explored in future research. Meta-analysis findings align with the hypothesis that TB may be associated with abnormal vascular function, and both local and systemic levels of VEGF can be used to trace this abnormality.

The Yin and Yang of toll-like receptors in endothelial dysfunction.

Endothelial cells (ECs) play a critical role in health and disease due to their widespread distribution and unique location. Although ECs are not regarded as classical immune cells, they actively participate in innate immune and inflammatory responses. EC function is affected by exogenous activators (i.e., infectious agents) and endogenous triggers (i.e., damage-associated molecular pattern molecules (DAMPs) released by stressed or injured cells). Toll-like receptors (TLRs) can recognize both infectious agents and DAMPs and play a key role in activating innate mechanisms in ECs. Endothelial dysfunction (EDF) may lead to tissue damage in various inflammatory and autoimmune diseases through TLRs. This review summarizes the current knowledge about the role of TLRs in a variety of EDF-related conditions, including autoimmunity and graft rejection, cancer, cardiovascular diseases, diabetes and related complications, ischemia and related injuries, and sepsis.

Central Inflammatory Cytokines in Tuberculous Meningitis: A Systematic Review and Meta-analysis.

No formal agreement exists regarding central inflammatory cytokine aberrations in tuberculosis (TB). We undertook a systematic review and meta-analysis of studies comparing cytokine levels in cerebrospinal fluid (CSF) from patients with TB compared with controls. We searched PubMed, Scopus, and Web of Science for articles published up to June 22, 2021. Studies were included in the meta-analysis if they assessed unadjusted levels of cytokines in unstimulated CSF samples and drew the comparison(s) between any of the following pairs: patients with TB versus controls without central nervous system (CNS) infection and meningitis, patients with TB versus patients with meningitis of etiologies other than Mycobacterium tuberculosis, HIV-infected patients with TB versus HIV-uninfected patients with TB, and HIV-infected patients with TB versus HIV-infected patients without TB. The primary outcome was the difference in mean CSF inflammatory cytokine levels between each of the 2 groups mentioned. The standardized mean difference was chosen to measure effect using a restricted maximum-likelihood estimator random-effects model. Of 1170 records identified, 40 studies were included in the meta-analysis. We calculated effect sizes for 30 different cytokines. About half of the studies took place in South Africa and India (18 out of 40 studies). Studies were mostly (92.5%) on patients with tuberculous meningitis (TBM), with only 3 articles of patients with neurotuberculosis and spinal TB. The quality of studies was rated as low to moderate and high with a 1.2:1 ratio. Compared with controls without CNS infection and meningitis, interferon-gamma (IFNγ), interleukin (IL)-12p40, IL-17F, IL-1ß, IL-2, IL-4, IL-6, IL-8, sIL-2R, transforming growth factor beta (TGFß), TGFß1, and tumor necrosis factor alpha (TNFα) were increased in patients with TBM. Compared with patients with meningitis of etiologies other than M. tuberculosis or combined meningitis and nonmeningitis patients, patients with TBM had higher CSF concentrations of IFNγ, IL-13, and sIL-2R, whereas levels of IL-12p70, IL-15, IL-1Ra, IL-5, IL-7, IL-9, and sTNFR55 were decreased. Compared with patients with meningitis of bacterial etiologies other than M. tuberculosis, CSF levels of IFNγ and sIL-2R were increased in patients with TBM, whereas levels of IL-1Ra, IL-13, IL-17, and TNF R55-BP were decreased. Patients with TBM were not different from patients with CM for most CSF cytokines assessed, but IFNγ and IL-1ß were increased. TNFα, IL-1ß, IL-1Ra, IL-8, IFNγ, sIL-2R, IL-13, and IL-17 were higher in patients with TBM than those with viral or aseptic meningitis. Compared with HIV-negative patients with TBM, IFNγ, IL-10, IL-12p70, and IL-5 were decreased in HIV-positive patients with TBM, whereas IL-1ß, TNFα, and IL-2 were increased. Elevated TNFα, IL-1ß, IFNγ, IL-6, IL-17, and IFNα2 were found in HIV-positive patients with TBM compared with their counterparts without TBM. This study should be considered an explorative meta-analytic review, leading us to offer the best TBM-associated central inflammatory cytokines. Our study could prepare a panel of central cytokines as a potential aid in diagnosing TBM and its differentiation from meningitis of other etiologies.

Adverse events associated with immune checkpoint inhibitors in patients with breast cancer: A systematic review and meta-analysis.

BACKGROUND: Breast cancer is one of the most prevalent cancers with a high rate of mortality. Immune checkpoint inhibitors (ICIs) have shown promising results in breast cancer treatment. However, the incidences of adverse events (AEs) and immune-related AEs (irAEs) due to ICIs have not been investigated comprehensively. We aimed to determine any-grade and grade 3-5 AEs and irAEs of ICIs compared to the control group which were other conventional therapies in adults with breast cancer. METHODS: We included controlled clinical trials that involved ICIs in adults with breast cancer to assess AEs and irAEs of ICIs. We systematically searched PubMed, EMBASE, Scopus, Web of Science, the Cochrane Central Register of Controlled Trials, Clinical-Trials.gov, and metaRegister of Controlled Trials up to March 12, 2021. Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) was used for quality assessment. RESULTS: Nine studies, including 4687 participants met our inclusion criteria. Rash and infusion reaction were the two most frequent irAEs of any-grade and grade 3-5. Among irAEs, hyperthyroidism had the most prominent difference between the two groups in favor of ICIs followed by hypothyroidism and adrenal insufficiency. Among grade 3-5 and any-grade non-immune AEs, increased aspartate aminotransferase (RR = 1.91; 95% CI, 1.11-3.28) and cough (RR = 1.32; 95%CI, 1.11-1.57) had the highest RRs in favor of ICIs, respectively. The frequencies of overall any-grade and grade 3-5 irAEs were higher in the ICI group. CONCLUSION: The results showed that all the AEs and irAEs of all the categories were more prevalent with ICIs.

Anti-inflammatory and M2 macrophage polarization-promoting effect of mesenchymal stem cell-derived exosomes.

Mesenchymal stem cells (MSCs) are multipotent cells beneficial in regenerative medicine and tissue repair. The therapeutic potential of MSCs for inflammatory diseases and conditions is partly due to secreted exosomes. Exosomes are one group of extracellular vesicles with 50-150 nm in diameter. They can carry numerous molecules and introduce them to the recipient cells to produce various biological effects. Macrophages are classified into M1 and M2 subtypes based on their activation states. M1 macrophages release pro-inflammatory factors like tumor necrosis factoralfa (TNF-α), interleukin1alfa (IL-1α), interleukin1beta (IL-1ß), interleukin6 (IL-6), C-X-C motif chemokine ligand 9 (CXCL9), and C-X-C motif chemokine ligand 10 (CXCL10), while M2 macrophages secrete anti-inflammatory mediators including interleukin10 (IL-10), transforming growth factor beta (TGF-ß), C-C motif chemokine ligand 1 (CCL1), C-C motif chemokine ligand 17 (CCL17), C-C motif chemokine ligand 18 (CCL18), and C-C motif chemokine ligand 22 (CCL22). This review summarizes the effect of MSC-derived exosomes in the polarization of M2 macrophages, which their anti-inflammatory and immunomodulatory properties are potentially effective in inflammation diseases and conditions such as central nervous system (CNS) diseases, autoimmune diseases, inflammatory bowel disease, cardiomyopathy, graftversushost disease, kidney, liver, lung, and skin injuries.