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Turkish Journal of Medical Sciences 2023B-cell depletion with rituximab (RTX) is widely used as a rescue therapy in patients with systemic sclerosis (SSc). The aim herein was to analyze the progress of...
BACKGROUND/AIM
B-cell depletion with rituximab (RTX) is widely used as a rescue therapy in patients with systemic sclerosis (SSc). The aim herein was to analyze the progress of disease-related outcomes after RTX therapy in severe SSc patients.
MATERIALS AND METHODS
Included in this study were 27 SSc patients who were followed-up between 2012 and 2020 and received at least 1 cycle of RTX for active disease, despite receiving standard immunosuppressives (ISs). In addition to the European Scleroderma Study Group and European Scleroderma Trials and Research Group activity scores, Medsger's severity, and the recently developed Scleroderma Clinical Trials Consortium Damage Index values were evaluated initially and at 1 year after the first infusion. The progress of individual organ damage was also assessed at the end of the follow-up period (at least 6 months after the last infusion) using the data extracted from the medical records.
RESULTS
Disease activity and severity-improved and disease-related overall damage worsened after the first year of RTX therapy (p < 0.001, p = 0.008, and p = 0.005). Some of the disease-related organ damage had improved at the end of the follow-up period, indicating its reversibility. Overall damage scores ≥11 after the first year of RTX therapy were found to be associated with mortality (p = 0.035).
CONCLUSION
RTX contributed to reducing the activity and severity in SSc patients with severe disease, nonetheless the efficacy related to the damage was limited. High damage scores in the first year were found to be associated with mortality. Spontaneous progress of manifestations requiring a longer period to improve and irregular consecutive RTX courses might lead to difficulties in differentiation between activity and damage.
Topics: Humans; Rituximab; Scleroderma, Systemic; Female; Male; Middle Aged; Severity of Illness Index; Adult; Immunosuppressive Agents; Treatment Outcome; Immunologic Factors; Aged
PubMed: 38813512
DOI: 10.55730/1300-0144.5739 -
Turkish Journal of Medical Sciences 2023Due to the increasing mortality and morbidity rates in diabetes mellitus (DM), which is one of the biggest health problems of our age, many treatment modalities are...
Protective effects of swimming exercises and metformin on cardiac and aortic damage caused by a high-fat diet in obese rats with type 2 diabetes, by regulating the Bcl2/Bax signaling pathway.
BACKGROUND/AIM
Due to the increasing mortality and morbidity rates in diabetes mellitus (DM), which is one of the biggest health problems of our age, many treatment modalities are still being tried. The positive effects of metformin (MET) and physical exercise (EXE) on the pathophysiology of diabetes are well known. In this study, it was aimed to detail these positive effects of MET and EXE in combination on the basis of inflammation, apoptosis mechanisms, and endogen nesfatin-1 (NES-1) synthesis.
MATERIALS AND METHODS
Twenty-seven type 2 DM (DM-2) male Wistar Albino rats were divided into 4 groups, as the high-fat diet (HFD), MET, EXE, and MET+EXE groups. The total duration of the study was 3 months. At the end of the experiment, blood glucose and lipid profiles were measured. Histopathological evaluation was performed on the cardiac and aortic tissues and apoptotic markers were evaluated immunohistochemically. Inflammatory markers and NES-1 levels were analyzed by enzyme-linked immunosorbent assay.
RESULTS
The plasma glucose, homeostatic model evaluation-insulin resistance (HOMA-IR), low-density lipoprotein (LDL) levels increased, and high-density lipoprotein (HDL) levels decreased significantly in the HFD group. In the treatment groups, the glucose, HOMA-IR, LDL, NES-1 levels in the plasma, as well as tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, caspase-3 (Cas-3), Bcl-2-associated X protein (Bax), and histopathological findings of inflammation in tissues were decreased. Additionally, there was an increase in plasma insulin, HDL, and tissue B-cell lymphoma-2 and levels.
CONCLUSION
It was observed that the MET and EXE treatments in the DM-2 model reduced cellular damage mechanisms such as inflammation and apoptosis. The decrease in NES-1 levels was thought to be secondary to this antiinflammatory effect. In conclusion, the results demonstrated the effectiveness of EXE in reducing DM-2 and the NES-1 levels. Further studies are needed to evaluate the effect in different EXE models and treatment durations.
Topics: Animals; Metformin; Diet, High-Fat; Diabetes Mellitus, Type 2; Rats, Wistar; Male; Rats; Signal Transduction; Proto-Oncogene Proteins c-bcl-2; Swimming; bcl-2-Associated X Protein; Obesity; Physical Conditioning, Animal; Hypoglycemic Agents; Apoptosis; Aorta; Nucleobindins; Diabetes Mellitus, Experimental
PubMed: 38813486
DOI: 10.55730/1300-0144.5727 -
Frontiers in Bioscience (Landmark... May 2024Developing a novel COVID-19 multi-epitope vaccine (CoVMEV) is essential to containing the SARS-CoV-2 pandemic.
BACKGROUND
Developing a novel COVID-19 multi-epitope vaccine (CoVMEV) is essential to containing the SARS-CoV-2 pandemic.
METHODS
The virus's immunodominant B and T cell epitopes from the S protein were found and joined to create the CoVMEV. Bioinformatics techniques were used to investigate the secondary and tertiary structures, as well as the physical and chemical properties of CoVMEV.
RESULTS
CoVMEV exhibited high antigenicity and immunogenicity scores, together with good water solubility and stability. Toll-like receptor 2 (TLR2) and toll-like receptor4 (TLR4), which are critical in triggering immunological responses, were also strongly favoured by CoVMEV. Molecular dynamics simulation and immune stimulation studies revealed that CoVMEV effectively activated T and B lymphocytes, and increased the number of active CD8+ T cells than similar vaccines.
CONCLUSION
CoVMEV holds promise as a potential vaccine candidate for COVID-19, given its robust immunogenicity, stability, antigenicity, and capacity to stimulate a strong immune response. This study presents a significant design concept for the development of peptidyl vaccines targeting SARS-CoV-2. Further investigation and clinical trials will be crucial in assessing the efficacy and safety of CoVMEV as a potential vaccine for COVID-19.
Topics: COVID-19 Vaccines; Humans; Spike Glycoprotein, Coronavirus; SARS-CoV-2; Epitopes, T-Lymphocyte; COVID-19; Epitopes, B-Lymphocyte; Computational Biology; Molecular Dynamics Simulation; Toll-Like Receptor 2; Toll-Like Receptor 4; Immunogenicity, Vaccine; CD8-Positive T-Lymphocytes; Immunoinformatics
PubMed: 38812300
DOI: 10.31083/j.fbl2905196 -
BMC Medical Genomics May 2024Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease. According to large-scale RNA sequencing (RNA-seq) data, B-ALL patients can be...
Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease. According to large-scale RNA sequencing (RNA-seq) data, B-ALL patients can be divided into more than 10 subgroups. However, many genomic defects associated with resistance mechanisms have not yet been identified. As an individual clinical tool for molecular diagnostic risk classification, RNA-seq and gene expression pattern-based therapy could be potential upcoming strategies. In this study, we retrospectively analyzed the RNA-seq gene expression profiles of 45 children whose molecular diagnostic classifications were inconsistent with the response to chemotherapy. The relationship between the transcriptome and chemotherapy response was analyzed. Fusion gene identification was conducted for the included patients who did not have known high-risk associated fusion genes or gene mutations. The most frequently detected fusion gene pair in the high-risk group was the DHRSX duplication, which is a novel finding. Fusions involving ABL1, LMNB2, NFATC1, PAX5, and TTYH3 at onset were more frequently detected in the high-risk group, while fusions involving LFNG, TTYH3, and NFATC1 were frequently detected in the relapse group. According to the pathways involved, the underlying drug resistance mechanism is related to DNA methylation, autophagy, and protein metabolism. Overall, the implementation of an RNA-seq diagnostic system will identify activated markers associated with chemotherapy response, and guide future treatment adjustments.
Topics: Humans; Child; Male; Female; Child, Preschool; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Sequence Analysis, RNA; Adolescent; Drug Resistance, Neoplasm; Infant; Retrospective Studies; Oncogene Proteins, Fusion
PubMed: 38811988
DOI: 10.1186/s12920-024-01892-w -
Signal Transduction and Targeted Therapy May 2024Conventional type 1 dendritic cells (cDC1) are the essential antigen-presenting DC subset in antitumor immunity. Suppressing B-cell lymphoma 9 and B-cell lymphoma 9-like...
Conventional type 1 dendritic cells (cDC1) are the essential antigen-presenting DC subset in antitumor immunity. Suppressing B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) inhibits tumor growth and boosts immune responses against cancer. However, whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely understood. Here, we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into tumor. Pharmacological inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8 T cell responses. Mechanistically, targeting BCL9/BCL9L promoted antigen presentation in tumors. This is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 axis. Importantly, using single-cell transcriptomics analysis, we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type (WT) cDC1 at activation and antigen presentation via NF-κB/IRF1 signaling. Together, we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens, as well as CD8 T cell activation and tumor infiltration. Targeting BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.
Topics: Animals; Mice; Dendritic Cells; Antigen Presentation; Transcription Factors; Mice, Knockout; CD8-Positive T-Lymphocytes; Humans; Neoplasms; Receptors, Chemokine
PubMed: 38811552
DOI: 10.1038/s41392-024-01838-9 -
Nature Communications May 2024Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the...
Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.
Topics: Receptors, CXCR4; Humans; Animals; Signal Transduction; Drug Resistance, Neoplasm; Dexamethasone; Type C Phospholipases; Cell Line, Tumor; Glucocorticoids; Mice; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Mice, Inbred NOD; Cell Survival
PubMed: 38811530
DOI: 10.1038/s41467-024-48818-9 -
Drug Metabolism and Disposition: the... May 2024Current therapeutic strategies for esophageal cancer (EC) patients have yielded limited improvements in survival rates. Recent research has highlighted the influence of...
Current therapeutic strategies for esophageal cancer (EC) patients have yielded limited improvements in survival rates. Recent research has highlighted the influence of drug metabolism enzymes (DME) on both drug response and EC development. Our study aims to identify specific DMEs regulated by histone acetylation and to elucidate its molecular and clinical features. CYP4F12 exhibited a notable upregulation subsequent to TSA treatment as evidenced by RNA-seq analysis conducted on the KYSE-150 cell line. The change in gene expression was associated with increased acetylation level of histone 3 K18 and K27 in the promoter. The regulation was dependent on p300. In silicon analysis of both TCGA-ESCA and GSE53624 dataset suggested a critical role of CYP4F12 in EC development as CYP4F12 was downregulated in tumor tissues and predicted better disease-free survival. Gene ontology analysis has uncovered a robust correlation between CYP4F12 and processes related to cell migration, as well as its involvement in cytosine-mediated immune activities. Further investigation into the relationship between immune cells and CYP4F12 expression has indicated an increased level of B cell infiltration in samples with high CYP4F12 expression. CYP4F12 was also negatively correlated with the expression of inhibitory checkpoints. An accurate predictive nomogram model was established combining with clinical factors and CYP4F12 expression. In conclusion, CYP4F12 was crucial in EC development, targeting CYP4F12 may improve the therapeutic efficacy of current treatment in EC patients. CYP4F12 expression was downregulated in EC patients and could be induced by TSA. During EC development, CYP4F12 was linked to reduced cell migration and increased infiltration of B cells. CYP4F12 also is a biomarker as prognostic predictors and therapeutic guide in EC patients.
PubMed: 38811154
DOI: 10.1124/dmd.124.001674 -
Frontiers in Immunology 2024In classical Hodgkin lymphoma (cHL), the survival of neoplastic cells is mediated by the activation of NF-κB, JAK/STAT and PI3K/Akt signaling pathways. CK2 is a highly...
INTRODUCTION
In classical Hodgkin lymphoma (cHL), the survival of neoplastic cells is mediated by the activation of NF-κB, JAK/STAT and PI3K/Akt signaling pathways. CK2 is a highly conserved serine/threonine kinase, consisting of two catalytic (α) and two regulatory (β) subunits, which is involved in several cellular processes and both subunits were found overexpressed in solid tumors and hematologic malignancies.
METHODS AND RESULTS
Biochemical analyses and assays showed an impaired expression of CK2 subunits in cHL, with CK2α being overexpressed and a decreased expression of CK2β compared to normal B lymphocytes. Mechanistically, CK2β was found to be ubiquitinated in all HL cell lines and consequently degraded by the proteasome pathway. Furthermore, at basal condition STAT3, NF-kB and AKT are phosphorylated in CK2-related targets, resulting in constitutive pathways activation. The inhibition of CK2 with CX-4945/silmitasertib triggered the de-phosphorylation of NF-κB-S529, STAT3-S727, AKT-S129 and -S473, leading to cHL cell lines apoptosis. Moreover, CX-4945/silmitasertib was able to decrease the expression of the immuno-checkpoint CD274/PD-L1 but not of CD30, and to synergize with monomethyl auristatin E (MMAE), the microtubule inhibitor of brentuximab vedotin.
CONCLUSIONS
Our data point out a pivotal role of CK2 in the survival and the activation of key signaling pathways in cHL. The skewed expression between CK2α and CK2β has never been reported in other lymphomas and might be specific for cHL. The effects of CK2 inhibition on PD-L1 expression and the synergistic combination of CX-4945/silmitasertib with MMAE pinpoints CK2 as a high-impact target for the development of new therapies for cHL.
Topics: Humans; Hodgkin Disease; Casein Kinase II; Signal Transduction; B7-H1 Antigen; Cell Line, Tumor; Phenazines; Naphthyridines; Apoptosis; Gene Expression Regulation, Neoplastic; Phosphorylation
PubMed: 38807597
DOI: 10.3389/fimmu.2024.1393485 -
BMC Medical Genomics May 2024Ovarian cancer is the most common cause of gynecological cancer death. Pak4 has been proved to be tumorigenic in many types of cancers, but its role in ovarian cancer is...
BACKGROUND
Ovarian cancer is the most common cause of gynecological cancer death. Pak4 has been proved to be tumorigenic in many types of cancers, but its role in ovarian cancer is still not clarified.
METHODS
In this study, we used immunohistochemistry to investigate into Pak4 expression in different histological types of ovarian cancer. TIMER, TISCH2, GEPIA, ualcan, KM plotter, GSCA and GeneMANIA were used to identify the prognostic roles and gene regulation networks of Pak4 in ovarian cancer. Immune infiltration levels were investigated using TIMER database.
RESULTS
Pak4 was highly expressed in ovarian cancers, regardless of different FIGO stages and histological grades. Single cell sequencing database proved that Pak4 was highly expressed in malignant ovarian cancer cells. Pak4 level was significantly correlated with different histological types of ovarian cancer. Pak4 expression was negatively connected with OS and PFS of ovarian cancer patients. Functions of Pak4 and its interacted genes were mainly involved in protein serine/threonine kinase activity, regulation of actin filament-based process and regulation of cytoskeleton organization. Pak4 level was negatively correlated with immune biomarkers of B cell infiltration (p = 2.39e-05), CD8 + T cell infiltration (p = 1.51e-04), neutrophil (p = 1.74e-06) and dendritic cell (p = 4.41e-08). Close correlation was found between Pak4 expression and T cell exhaustion (p < 0.05).
CONCLUSIONS
Our results demonstrated the expression level, gene interaction networks and immune infiltration levels of Pak4 in ovarian cancer. And the results revealed role of Pak4 in tumorigenesis and the possibility to be a potential immunotherapeutic target.
Topics: Humans; p21-Activated Kinases; Female; Ovarian Neoplasms; Gene Expression Regulation, Neoplastic; Prognosis; Carcinogenesis; Biomarkers, Tumor; Lymphocytes, Tumor-Infiltrating; Gene Regulatory Networks
PubMed: 38807162
DOI: 10.1186/s12920-024-01917-4 -
Database : the Journal of Biological... May 2024In the field of complex autoimmune diseases such as systemic lupus erythematosus (SLE), systems immunology approaches have proven invaluable in translational research...
In the field of complex autoimmune diseases such as systemic lupus erythematosus (SLE), systems immunology approaches have proven invaluable in translational research settings. Large-scale datasets of transcriptome profiling have been collected and made available to the research community in public repositories, but remain poorly accessible and usable by mainstream researchers. Enabling tools and technologies facilitating investigators' interaction with large-scale datasets such as user-friendly web applications could promote data reuse and foster knowledge discovery. Microarray blood transcriptomic data from the LUPUCE cohort (publicly available on Gene Expression Omnibus, GSE49454), which comprised 157 samples from 62 adult SLE patients, were analyzed with the third-generation (BloodGen3) module repertoire framework, which comprises modules and module aggregates. These well-characterized samples corresponded to different levels of disease activity, different types of flares (including biopsy-proven lupus nephritis), different auto-antibody profiles and different levels of interferon signatures. A web application was deployed to present the aggregate-level, module-level and gene-level analysis results from LUPUCE dataset. Users can explore the similarities and heterogeneity of SLE samples, navigate through different levels of analysis, test hypotheses and generate custom fingerprint grids and heatmaps, which may be used in reports or manuscripts. This resource is available via this link: https://immunology-research.shinyapps.io/LUPUCE/. This web application can be employed as a stand-alone resource to explore changes in blood transcript profiles in SLE, and their relation to clinical and immunological parameters, to generate new research hypotheses.
Topics: Lupus Erythematosus, Systemic; Humans; Transcriptome; Internet; Databases, Genetic; Gene Expression Profiling; Software
PubMed: 38805754
DOI: 10.1093/database/baae045