Abstract B-cell–based immune cell therapies represent a potential strategy for restoring immune tolerance by expanding regulatory T cells (Tregs). CD4+Foxp3+ Tregs are essential for maintaining immune homeostasis and represent an attractive therapeutic target. However, clinically established strategies to safely and durably expand endogenous Tregs remain lacking. We previously identified IgDlow/- B cells as a splenic B-cell subset that promotes Treg expansion through a glucocorticoid-induced TNF receptor ligand (GITRL)–dependent mechanism, whereas other B cell populations do not. In B-cell–specific GITRL transgenic mice, Treg numbers are significantly increased, and the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, is attenuated. To evaluate the translational potential of this pathway as a hematopoietic immune cell therapy, we transplanted wild-type recipients with bone marrow from GITRL transgenic donors. After hematopoietic reconstitution, GITRL expression was selectively increased on B cells. This resulted in the expansion of endogenous Tregs and a corresponding increase in the proportion of Tregs within the CD4+ T-cell compartment, with near-complete suppression of EAE. These findings demonstrate that enhancing GITRL expression within the hematopoietic B-cell compartment provides a tractable strategy for expanding endogenous Tregs and augmenting Treg-mediated immune suppression, establishing a framework for developing B-cell–based immune cell therapies capable of durable immune suppression for inflammatory diseases.

This study aims to compare the effectiveness of leadless pacemakers (LPs) and transvenous pacemakers and to examine the safety of both methods. We included patients undergoing single-chamber pacemaker implantation, either LP or TVP. Our outcomes were successful implantation rate, major complication, vascular injury, tamponade, and pneumothorax. We performed a double-arm analysis comparing LP versus TVP, with risk ratio (RR) and 95% confidence interval. A total of 10 studies were included in this meta-analysis. Regarding efficacy endpoints, RR revealed no significant difference between the LP and transvenous pacemaker groups in terms of successful rate of implantation (RR = 1.00; P = 0.77). Regarding safety outcomes, LP experienced lower incidence of major complications (RR = 0.47; P = 0.01), infection (RR = 0.24; P = 0.001), and tamponade (RR = 0.36; P = 0.01). There was no significant difference between both groups regarding pneumothorax (RR = 0.35; P = 0.22) and vascular injury (RR = 1.55; P = 0.25). The study findings suggest that both LPs and TVPs have similar effectiveness. Moreover, the incidences of pneumothorax, vascular injuries, and major complications were found to be comparable between the 2 methods. However, LPs were found to have lower rates of infection and tamponade.

In the immunological surveillance against cancer, natural killer (NK) cells are essential effectors that help eradicate altered cells. The complex interactions that occur between NK cells and the tumor microenvironment (TME) are thoroughly examined in this review. The review examines how cytokine stimulation affects NK cell activation, focusing on the dynamic modulation of NK cell function within the TME. It looks at NK cell-related biomarkers such as PD-1/PD-L1, methylation HOXA9 (Homeobox A9), Stroma AReactive Invasion Front Areas (SARIFA), and NKG2A/HLA-E, providing critical information about prognosis and treatment outcomes. The changing landscape of immunotherapies—including checkpoint inhibitors, CAR-NK cells, and cytokine-based interventions—is examined in the context of enhancing NK cell activity. The review highlights the potential pathways for precision medicine going forward, focusing on customized immunotherapies based on unique biomarker profiles and investigating combination medicines to produce more robust anti-tumor responses.

Abstract CD4+Foxp3+ T regulatory cells (Treg) are well characterized for their role in controlling autoimmunity. We have previously shown that mice deficient in B cells (μMT) have significantly reduced Treg and cannot recover from the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), demonstrating a regulatory role for B cells in immune tolerance. Using B cell depletion strategies and phenotyping, we discovered B cell IgD Low (BDL) regulatory B cells that when adoptively transferred into μMT mice increased Treg numbers and drove EAE recovery. BDL activity was found to be dependent upon glucocorticoid-induced tumor necrosis factor receptor-related protein ligand (GITRL), which engages GITR on Treg inducing their proliferation. To investigate whether BDL activity could be enhanced, B cell-specific GITRL transgenic (tg) mice were obtained. These mice had three-fold more Treg than WT mice consistent with attenuated EAE. Adoptive transfer of GITRLtg BDL into μMT mice did not increase Treg numbers nor reduce EAE severity as compared to WT BDL. Here we posit that sustaining elevated Treg numbers is required to ameliorate EAE to clinical scores below that of WT, as seen in GITRLtg mice. This holds translational implications for many autoimmune diseases for which Treg cell therapies have been proposed. New approaches must be examined to not only increase Treg in autoimmune patients, but also to retain these levels over longer periods of time.

Background: Bile acid malabsorption (BAM) is characterized by chronic watery diarrhea resulting from excessive bile acids in the feces. BAM is often an overlooked cause of chronic diarrhea, with its prevalence not being sufficiently researched. This review aimed to assess existing literature that explores diverse treatment strategies, to review the published studies that examine the various therapies for BAM patients, emphasizing their influence on clinical results. Methods: We conducted a comprehensive review of various databases, including PubMed, Scopus, Web of Science, Cochrane Database, and EMBASE. Our criteria for inclusion focused on randomized controlled studies (RCTs) that evaluated the effectiveness of different treatment options for patients with BAM. To rank the treatments, we adopted the frequentist approach through the "netrank" function of the network meta -analysis (NMA). Moreover, we utilized the "netsplit" function in the NMA to separate direct and indirect evidence. Our analysis was carried out using RStudio version 1.4.1717 (2009 - 2021 RStudio, Inc.), and we used the "netmeta" and "meta" packages for NMA. Results: We found seven relevant articles involving 213 participants, the average age being approximately 50 years, including 53 males and 92 females. Of the drugs examined, tropifexor was proved to be the most effective in raising the fibroblast growth factor 19 (FGF19) levels and reducing the 7 alpha-hydroxy-4-cholesten-3-one (C4) levels, compared to the placebo (mean difference (MD) = 335.30, 95% confidence interval (CI) (334.86, 335.74), MD = -24.60, 95% CI (-25.37, -23.83); respectively). Compared to colesevelam and the placebo, liraglutide was more efficient in decreasing fecal bile acid concentration (liraglutide; MD = -19, 95% CI (-37.61, -0.39)). Conclusions: Tropifexor has been identified as the most successful medication in mitigating BAM symptoms. To ensure more accurate results, there is a need for randomized controlled clinical trials that involve a larger participant pool.

Background: Diabetes mellitus (DM) challenges health and quality of life of patients, families, and communities.Patients with comorbid depression are more likely to develop macrovascular and microvascular complications.The aim was to assess glycemic control and adherence in diabetic patients with comorbid depression.Further, the study evaluated the relationship between adherence and the physician-patient relationship.Methods: The study was conducted at Al-Agouza Family Medicine Center (AFMC) between February 2018 and March 2020.The included patients were between 35 -80 years of age; had type 2 diabetes with hemoglobin A1c (HbA1c) ≥ 6.5%, fasting plasma glucose ≥ 126 mg/dl, and scored between 11 -30 on the Beck Depression Inventory (BDI).Logistic regression, chi-square, and analysis of variance (ANOVA) were used to assess the relationship between depression, adherence, physician-patient relationship, and other variables.Results: The study included 100 eligible patients with a median BDI score of 20 (10 -30).The median diabetic panel for patients was FBS 188 (126 -348) mg/dl, PPS 282.50 (162 -448) mg/dl, and HbA1c 9.5 (6.6 -14.0)%.Depression and regular follow-up visits were statistically associated with improvement of diabetes symptoms (p = 0.019).There was a significant relationship (p < 0.001) between adherence, regular follow-up visits, and knowledge of DM.Further, there was a significant relationship between the physician-patient relationship and DM improvement (p = 0.047).Conclusion: Physician-patient relationship was paramount to improving adherence and positive diabetes care.Our findings suggest a shift to a physician-patient relationship model with mutual agreement on medical decisions is highly recommended.

Diltiazem (DTZ) is one of the most effective medications for treating cardiovascular diseases. It has been widely used for the treatment of angina pectoris, hypertension and some types of arrhythmia. The development and application of a modified carbon paste sensor with improved detection limits for the potentiometric determination of diltiazem are the main goals of the current study. Sensitivity, long-term stability, reproducibility and improving the electrochemical performance are among the characteristics that have undergone careful examination. A modified carbon paste sensor based on β-cyclodextrin (β-CD) as ionophore, a lipophilic anionic additive (NaTPB) and a ZnO-decorated polyaniline/coal nanocomposite (ZnO@PANI/C) dissolved in dibutyl phthalate plasticizer, exhibited the best performance and Nernstian slope. The ZnO@PANI/C based sensor succeeded in lowering the detection limit to 5.0 × 10-7 through the linear range 1.0 × 10-6 to 1.0 × 10-2 mol L-1 with fast response time ≤ 10.0 s. The prepared nanomaterial was characterized using X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). The surface properties of the proposed sensor were characterized by electrochemical impedance spectroscopy (EIS). The selectivity behavior of the investigated sensor was tested against a drug with similar chemical structure and biologically important blood electrolytes (Na+, K+, Mg2+, and Ca2+). The proposed analytical method was applied for DTZ analysis in pure drug, pharmaceutical products and industrial water samples with excellent recovery data.

Abstract In silico methods such as molecular docking and molecular dynamic (MD) simulations have significant interest due to their ability to identify the protein-ligand interactions at the atomic level. In this work, different computational methods were used to elucidate the ability of some olive oil components to act as Neisseria adhesion A Regulatory protein (NadR) inhibitors. The frontier molecular orbitals (FMOs) and the global properties such as global hardness, electronegativity, and global softness of ten olive oil components (α-Tocopherol, Erythrodiol, Hydroxytyrosol, Linoleic acid, Apigenin, Luteolin, Oleic acid, Oleocanthal, Palmitic acid, and Tyrosol) were reported using Density Functional Theory (DFT) methods. Among all investigated compounds, Erythrodiol, Apigenin, and Luteolin demonstrated the highest binding affinities (−8.72, −7.12, and −8.24 kcal/mol, respectively) against NadR, compared to −8.21 kcal/mol of the native ligand based on molecular docking calculations. ADMET properties and physicochemical features showed that Erythrodiol, Apigenin, and Luteolin have good physicochemical features and can act as drugs candidate. Molecular dynamics (MD) simulations demonstrated that Erythrodiol, Apigenin, and Luteolin show stable binding affinity and molecular interaction with NadR. Further Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analyses using the MD trajectories also demonstrated the higher binding affinity of Erythrodiol, Apigenin and Luteolin inside NadR protein. The overall study provides a rationale to use Erythrodiol, Apigenin, and Luteolin in the drug development as anti-adhesive drugs lead. Communicated by Ramaswamy H. Sarma

BACKGROUND:Overexpression of CD200 in ALL patients indicates that it may be useful in the characterization of leukemia initiating cells (LIC). We aim at investigating the expression pattern of CD200 on leukemic B cells and the correlation of CD200 expression with various clinical and laboratory findings in 62 newly diagnosed acute lymphoblastic leukemia patients.METHODS:All patients were subjected to full history taking, a thorough clinical examination, and laboratory investigations, which included complete blood count (CBC), BM aspiration, immunophenotyping of blast cells, and CD200 expression.RESULTS:There is a higher statistically significant mean value of CD200 expression among the cases (66.15 ± 23.08) than the control group (0.37 ± 0.2) (p value ≤ 0.001). CD200 expression shows a significant correlation with total leucocytic count and hemoglobin level (p = 0.001, 0.03, respectively).CONCLUSIONS:This study showed that CD200 expression was expressed in 100% of the patients. Correlations between CD200 expression and different laboratory data of patients revealed that there was an impact of CD200 on different diagnostic findings. After the follow-up of the patients, we found that the use of PRISM function of the software could add value to the detection of minimal residual disease.

Background: Glaucoma is one of the leading causes that lead to blindness worldwide.Purpose: To compare the outcomes of sub-scleral trabeculectomy (SST) with subconjunctival Bevacizumab versus Mitomycin-C (MMC) in cases with bilateral primary open angle glaucoma (POAG).Study design: case series comparative study.Methods: We collected data from 60 eyes of 30 patients that were diagnosed as POAG and treated with SST and adjunctive therapy was used either with subconjunctival bevacizumab or topical intraoperative mitomycin-C, in the period from January 2021 to February 2022.We analyzed outcomes of this procedure as intraocular pressure (IOP), glaucoma medications reduction and bleb related complications.Results: The preoperative IOP improved significantly from 29.86±4.86mm Hg to 11.8±2.17mm Hg at 6th month and to 12.03±1.99mmHg at the last follow-up in the bevacizumab group, and from 31.3±4.03mm Hg to 10.8±2.24 mm Hg at 6th month and to 11.4±2.91 mm Hg after one year of follow-up in the MMC group.Both arms showed a significant decrease in the number of antiglaucoma eye drops used at 6 months compared with the preoperative data.In both groups, bleb show a horizontal extension of 2-3 hours, low to moderate height and mild to moderate vascularization.Conclusions: Trabeculectomy with adjunctive Bevacizumab is an effective and safe procedure in patients with POAG.The outcome of SST with MMC and with Bevacizumab was similar in lowering IOP.The complication rates were higher in MMC group than the Bevacizumab group.Bevacizumab is preferred in high risk bleb failure cases.

This study evaluated the efficacy of IgE in predicting disease progression in chronic hepatitis B virus (HBV) and HBV related hepatocellular carcinoma (HCC) compared to normal controls. The study included 60 HBV-infected patients. Of these, 30 patients with chronic hepatitis B but not related to HCC and 30 patients with related HCC. Serum level of IgE was measured by ELISA. Serum level of IgE was higher in HCC patients than non-HCC patients (p < 0.005). Significant correlations were detected between IgE, transaminases (ALT, AST), alpha-fetoprotein and severity scores in chronic hepatitis B (CHB) patients. The level of IgE was correlated with HB viral load. Stronger correlations were evident between IgE, prothrombin time and total bilirubin. In conclusion, IgE levels may be considered as non-invasive markers for monitoring liver disease progression in CHB.

Background Damage occurs in the brain tissue in MS which appears normal on standard conventional imaging (normal appearing brain tissue). This slow, evolving damage can be monitored by nonconventional advanced MR imaging techniques. New techniques for the measurement of cortical thickness have been validated against histological analysis and manual measurements. The aim of our study was to study the role of MRI surface-based analysis and cortical thickness measurement in the evaluation of patients with Relapsing Remitting Multiple Sclerosis and to detect if there is localized rather than generalized cortical atrophy in Multiple Sclerosis patients and correlating these findings with clinical data. Results 30 patients and 30 healthy control were included in this study and they were subjected to cortical thickness analysis using MRI. The patients in our study showed decreased thickness of the precentral, paracentral, postcentral, posterior cingulate cortices and mean cortical thickness in both hemispheres when compared with the normal control group. Statistical analysis was significant ( P value < 0.05) for the precentral, paracentral, postcentral, posterior cingulate cortices and mean cortical thickness in both hemispheres. On the other hand, statistical analysis was not significant ( P value > 0.05) for other cortices. There was a significant negative correlation between the precentral, paracentral, postcentral, posterior cingulate cortices and mean cortical thickness in both hemispheres and EDSS scores with correlation coefficients ranging from − 0.9878 to − 0.7977. Conclusions MRI and post-processing segmentation analysis for cortical thickness is non-invasive imaging techniques that can increase the level of diagnostic confidence in diagnosis of MS patients and should be included as routine modality when evaluating patients with MS.

Background The COVID-19 pandemic has led to a global crisis, creating an unprecedented situation, which has taken the world by storm, overshadowing on all life' aspects and having a significant impact on the health systems of most countries. In this study, the delivery of health services is investigated both before and during the outbreak of the COVID-19 pandemic at public hospitals in Yemen to assess the impact of COVID-19 on the utilisation of health services. Method Data collected from 127 hospitals in Yemen were reviewed using the DHIS2 system. The data represented 3 months before the outbreak of COVID-19 between January and March 2020 and during the outbreak of COVID-19 outbreak between April and June 2020. The results were then compared with the same period in 2019. The utilisation pattern of healthcare services during the period of investigation was compiled and analysed by applying a generalised estimating equation (GEE) to examine the effects of the COVID-19 outbreak in Yemen. The data collected from the targeted hospitals included information related to consultations, surgeries, deliveries, C-sections and penta-3rd dose immunisation. Results The trendline of health services used during the pandemic showed a gradual decline beginning from April 2020 for consultations, surgeries and penta-3rd dose utilisation. The GEE model revealed a significant effect (p<0.05) during the outbreak compared with preoutbreak in the consultation services (B=-1,343.9; 95% CI -1,767.2 to -920.6; chi(2)=38.718), surgeries (B=-54.98; 95% CI -79.13 to -30.83, chi(2)=19.911) and penta-3rd dose (B=-24.47; 95% CI -30.56 to -18.38 and chi(2)=62.010). As for deliveries and C-sections, the results were shown to be statistically non-significant. Conclusion The impact of COVID-19 on continuity of health services delivery in Yemen has been distinct and profound, where the study revealed that the number of the consultations, surgeries and number of vaccinated children have been declined during the COVID-19 pandemic, likely due to the partially lockdown measures taken and fear of being infected. However, the deliveries and C-section services remained nearly in the same level and did not affect by the COVID-19 pandemic.

Background: The relation between depression and diabetes is bidirectional and both can lead to morbidity and mortality. Despite the success of Cognitive Behavioral Therapy (CBT) in managing psychiatric comorbidities, research on its use in the treatment of comorbid diabetes and depression is limited and with varying results. The aim of the study is to assess the efficacy of CBT on depressed patients with type 2 diabetes. Methods: This randomized controlled trial was conducted at an urban primary healthcare center in Egypt from February 2019 to March 2020 and included 80 participants. Key inclusion criteria were uncontrolled type 2 diabetes (T2D) (HbA1c >7.5%) and depression symptoms diagnosed by Beck’s Depression Index. Participants were assessed for all battery of instruments. Subsequently, participants were randomized to control and treatment groups. The treatment group received four CBT sessions. Both groups received a thirty-minute structured diabetes education and their usual diabetes treatment. Three months later, all participants were reassessed for depression and diabetes compliance and all labs were performed post intervention. Both the primary (the difference in HbA1c pre-post intervention) and secondary outcomes (the change in depressive symptoms assessed) were analyzed using ANCOVA. Results: Both groups were matching at baseline. Post intervention, the CBT group revealed a significant reduction in depressive symptoms while adjusting for Beck Depression Index (BDI) pre-intervention [F (1, 74) = 7.074, p = 0.010]. Moreover, HBA1c was improved significantly when controlling for pre-intervention BDI scores and BMI [F (1,73) = 4.27, p = 0.042] compared to the control group. Conclusions: The CBT program was both inexpensive and easily accessible. It could fit very well in primary care settings. The results indicated CBT intervention was effective in improving diabetes control and depression. However, a larger-scale study to test its effect on a larger scale population and its long-term impact is recommended.

Brain volume loss (BVL) is widespread in MS and occurs throughout the disease course at a rate considerably greater than in the general population. In MS, brain volume correlates with and predicts future disability, making BVL a relevant measure of diffuse CNS damage leading to clinical disease progression, as well as serving as a useful outcome in evaluating MS therapies. The aim of our study was to evaluate the role of automated segmentation and quantification of deep grey matter structures and white matter lesions in Relapsing Remitting Multiple Sclerosis patients using MR images and to correlate the volumetric results with different degrees of disability based on expanded disability status scale (EDSS) scores. All the patients in our study showed relative atrophy of the thalamus and the putamen bilaterally when compared with the normal control group. Statistical analysis was significant for the thalamus and the putamen atrophy (P value < 0.05). On the other hand, statistical analysis was not significant for the caudate and the hippocampus (P value > 0.05); there was a significant positive correlation between the white matter lesions volume and EDSS scores (correlation coefficient of 0.7505). On the other hand, there was a significant negative correlation between the thalamus and putamen volumes, and EDSS scores (correlation coefficients < − 0.9), while the volumes of the caudate and the hippocampus had a very weak and non-significant correlation with the EDSS scores (correlation coefficients > − 0.35). The automated segmentation and quantification tools have a great role in the assessment of brain structural changes in RRMS patients, and that it became essential to integrate these tools in the daily medical practice for the great value they add to the current evaluation measures.

Background MRI is the method of choice in the diagnosis of MS as well as in monitoring the disease activity. MRI volumetry is used to assess whole or regional brain volume loss which reflects neurodegenerative aspect of the disease and plays an important role in all stages of disease. The aim of this work is to study MRI volumetry in the evaluation of cerebellum and brain stem volume loss in RRMS patients and its correlation with neurological disability score and number of relapses. Results Volumes of whole brainstem, medulla, and pons showed a significant decrease in RRMS cases compared to controls ( p < 0.05). Brainstem volume had a mean volume of 22.17 and 25.09 cm 3 in cases and controls, respectively. However, midbrain volume showed no significant difference between cases and controls ( p = 0.134). Volume of left cerebellar cortex showed a significant decrease in RRMS cases compared to controls ( p < 0.001). It had mean volumes of 81.64 and 92.14 ml in cases and controls, respectively, at left cerebellar hemisphere, while right cerebellar hemisphere cortex volumes were 80.37 and 91.97 ml in cases and controls, respectively. Cerebellar white matter showed no significant volume decrease in cases and controls. Conclusion Volumetric MR imaging is an important tool for quantifying the MS disease, assesses MS activity, progression, and tissue loss. The degree and the pattern of atrophy on MRI images correlate significantly with the neurological disability score and number of relapses.

Mixed matrix membranes (MMMs) for reverse osmosis (RO) have become a significant target in various research. Herein, cellulose acetate membranes (CA) with Linde Type A (LTA) Zeolite Nanoparticles (ZNPs) were investigated as MMMs using the dry–wet phase inversion technique. Different percentages of LTA ZNPs were added to study their effect on the prepared MMMs. The hydrophilicity was studied by contact angle measurement. In addition, the performance of the MMMs was investigated through the RO unit cell using 10,000 ppm NaCl solution. It was shown that the salt rejection was found to be 86.8%, with a permeate water flux of 1.78 L/m2 h at 10 bar with 0.09 g of ZNPs compared with the pristine CA membrane which had a 96.5% salt rejection with a permeate water flux of 1 L/m2 h. On the other hand, the highest salt rejection obtained by this nanocomposite was 95.5% with 0.07 g ZNPs and permeate water flux of 1.3 L/m2 h.

B-cell IgD Low (BDL) B cells have been shown to promote immunological tolerance by inducing proliferation of CD4+Foxp3+ T-regulatory cells (Treg) in a glucocorticoid-induced tumor necrosis factor receptor-related protein ligand (GITRL, Tnfsf18)-dependent manner. BDL cells constitute a small subset of splenic B lymphocytes that, in mice, are characterized by the B220+IgMintCD21intCD23+CD93-IgDlow/- cell surface expression profile. In this chapter, we show the flow cytometry gating strategy developed to identify and purify BDL. In addition, we describe an in vitro assay and two in vivo assays to assess BDL regulatory activity by quantitating Treg expansion/proliferation and indicate how they can be used in mouse models of disease. Collectively, these methods are useful to track and quantitate BDL and Treg numbers and assess their regulatory activity in inflammatory disease models.

Background: Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and metastasis, however their role in pediatric Acute lymphoblastic leukemia (ALL) is still unrevealed. Methods : The diagnostic, prognostic and predictive value of tissue inhibitor of metalloproteinase (TIMP-1), MMP-2, MMP-9 and CD34 + CD38 - CSCs were assessed in bone marrow (BM) samples of 76 ALL children using Flow Cytometry analysis. Results : There was a significant increase in TIMP-1 [1.52 (0.41-10) versus 0.91(0.6-1.12); respectively, P<0.001 ], and CSCs CD84+CD38- [1 (0.03-18.6) versus 0.3 (0.01-1.1), P<0.001] expression in ALL patients compared to controls. While there were no significant differences regarding MMP-2 and MMP-9 expression between the two groups. The sensitivity, specificity, AUC of MMP-2 were (80.3%, 53.3% and 0.568, P=0.404), and that of MMP-9 were (53.9%, 40% and 0.660, P=0.053). While that of TIMP-1 were (78.9%, 100% and 0.892, P<0.001) , and that of CSCs CD34+ CD38- were (78.9%, 73.3% and 0.855, P<0.001). There was a significant association between MMP-2 overexpression and MRD at day-15, increased BM blast cell count at diagnosis and at day-15, ( P=0.020, P=0.047 and P=0.001 ). Increased TIMP-1 expression associated with the high-risk disease (P<0.001) , increased BM blast cell count at diagnosis and at day-15 ( P=0.033 and P=0.001 ), as well as MRD at day 15 and day 42 (P<0.001 for both). CD34 + CD38 - CSCs associated with MRD at day-15 , increased BM blast cell count at diagnosis and at day-15 ( P=0.015, P=0.005 and P=0.003 ). TIMP-1 overexpression associated with shorter DFS and OS rates ( P=0.009 and P=0.048 ). Multivariate logistic regression analysis showed that both TIMP-1 [ OR: 4.224, P=0.046 ], and CD34+CD38- CSCs [ OR: 6.873, P=0.005 ] are independent diagnostic factors for pediatric ALL. Conclusion: TIMP-1 and CD34+CD38- CSCs could be useful independent diagnostic markers for pediatric ALL. Also, TIMP-1 is a promising prognostic marker for poor outcome of the patients.

It is now appreciated that in addition to their role in humoral immunity, B cells also exert regulatory mechanisms that lead to attenuation of inflammatory responses. The concept of B-cell regulation became well recognized when mice deficient in B cells due to genetic disruption were shown to be refractory to recovery from the signs of experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. This seminal study spurred the search for B-cell regulatory phenotypes and mechanisms of action. Our approach was to utilize differential B-cell depletion with anti-CD20 to retain B cells whose presence were required to achieve EAE recovery. Utilizing flow cytometry, adoptive cell therapy and genetic approaches, we discovered a new B-cell subset that, upon adoptive transfer into B cell-deficient mice, was sufficient to promote EAE recovery. This B-cell subset is IgM(+), but due to low/negative IgD cell surface expression, it was named B-cell IgD low (BDL). Mechanistically, we found that in the absence of BDL, the absolute cell number of CD4(+) Foxp3(+) T regulatory cells (Treg), essential for immune tolerance, was significantly reduced. Furthermore, we found that BDL expression of glucocorticoid-induced tumor necrosis factor ligand (GITRL) was essential for induction of Treg proliferation and maintenance of their homeostasis. Thus, we have identified a new B-cell subset that is critical for immunological tolerance through interactions with Treg. (C) 2020 Elsevier Ltd. All rights reserved.