Activity

During recent years considerable progress has been made in the treatment of multiple myeloma. However, despite the current improvements in the prognosis of this malignancy, it always ends with relapse, and therefore new therapy approaches for destroying resistant cancer cells are needed. Presently, there is great hope being placed in the use of immunotherapy against refractory/relapsed multiple myeloma which is unresponsive to any other currently known drugs. The most promising one is CAR-T cell therapy which has already shown tremendous success in treating other malignancies such as acute lymphoblastic leukaemia (ALL) and could potentially be administered to multiple myeloma patients. CAR-T cells equipped with receptors against BCMA (B-cell maturation antigen), which is a surface antigen that is highly expressed on malignant cells, are now of great interest in this field with significant results in clinical trials. Furthermore, CAR-T cells with other receptors and combinations of different strategies are being intensively studied. However, even with CAR-T cell therapy, the majority of patients eventually relapse, which is the greatest limitation of this therapy. Serious adverse events such as cytokine release syndrome or neurotoxicity should also be considered as possible side effects of CAR-T cell therapy. Here, we discuss the results of CAR-T cell therapy in the treatment of multiple myeloma, where we describe its main advantages and disadvantages. Additionally, we also describe the current results that have been obtained on using combinations of CAR-T cell therapies with other drugs for the treatment of multiple myeloma.Multiple myeloma (MM), a malignant neoplasm of plasma cells that reside in the bone marrow (BM), is universally preceded by a precursor state termed monoclonal gammopathy of undetermined significance (MGUS). Many individuals with MGUS never progress to MM or progress over many years. Therefore, MGUS provides a unique opportunity to surveil changes in the BM tumor microenvironment throughout disease progression. It is increasingly appreciated that MGUS cells carry many of the genetic changes found in MM. Prior studies have also shown that MGUS cells can be recognized by the immune system, leading to early changes in the BM immune environment compared to that of healthy individuals, including alterations in both innate and adaptive immunity. Progression to clinical MM is associated with attrition of T cells with stem memory-like features and instead accumulation of T cells with more terminally differentiated features. Recent clinical studies have suggested that early application of immune-modulatory drugs, which are known to activate both innate and adaptive immunity, can delay the progression to clinical MM. Understanding the biology of how the immune response and tumors coevolve over time is needed to develop novel immune-based approaches to achieve durable and effective prevention of clinical malignancy.

Murine monocytes (MC) are classified into Ly6C

and Ly6C

MC. Ly6C

MC is the pro-inflammatory subset and the counterpart of human CD14

CD16

intermediate MC which contributes to systemic and tissue inflammation in various metabolic disorders, including hyperhomocysteinemia(HHcy). This study aims to explore molecule signaling mediating MC subset differentiation in HHcy and control mice.

RNA-seq was performed in blood Ly6C

and Ly6C

MC sorted by flow cytometry from control and HHcy cystathionine β-synthase gene-deficient (

) mice. Transcriptome data were analyzed by comparing Ly6C

vs. Ly6C

in control mice, Ly6C

vs. Ly6C

in

mice,

Ly6C

vs. control Ly6C

MC and

Ly6C

vs. click here control Ly6C

MC by using intensive bioinformatic strategies. Significantly differentially expressed (SDE) immunological genes and transcription factor (TF) were selected for functional pathways and transcriptional signaling identification.

A total of 7,928 SDE genes and 46 canonical pathways derived from it nal models to describe Ly6C

to Ly6C

MC subset differentiation, immune checkpoint regulation, Ly6C

MC to MΦ subset differentiation and Ly6C

MC to lymphocyte functional adaptation.

Ly6C

MC displayed enriched inflammatory pathways and favored to be differentiated into MΦ. Ly6C

MC manifested activated T-cell signaling pathways and potentially can adapt the function of lymphocytes. HHcy reinforced inflammatory feature in Ly6C

MC and strengthened lymphocytes functional adaptation in Ly6C

MC.

Ly6Chigh MC displayed enriched inflammatory pathways and favored to be differentiated into MΦ. Ly6Clow MC manifested activated T-cell signaling pathways and potentially can adapt the function of lymphocytes. HHcy reinforced inflammatory feature in Ly6Chigh MC and strengthened lymphocytes functional adaptation in Ly6Clow MC.The recent outbreak of SARS-CoV2 has emerged as one of the biggest pandemics of our century, with outrageous health, social and economic consequences globally. Macrophages may lay in the center of COVID-19 pathogenesis and lethality and treatment of the macrophage-induced cytokine storm has emerged as essential. Specialized pro-resolving mediators (SPMs) hold strong therapeutic potentials in the management of COVID-19 as they can regulate macrophage infiltration and cytokine production but also promote a pro-resolving macrophage phenotype. In this review, we discuss the homeostatic functions of SPMs acting directly on macrophages on various levels, towards the resolution of inflammation. Moreover, we address the molecular events that link the lipid mediators with COVID-19 severity and discuss the clinical potentials of SPMs in COVID-19 immunotherapeutics.We analyzed in a cohort of 68,606 first deceased donor kidney transplantations reported to the Collaborative Transplant Study whether an epitope-based matching of donor-recipient pairs using the Predicted Indirectly ReCognizable HLA Epitopes algorithm (PIRCHE-II) is superior to currently applied HLA antigen matching. PIRCHE-II scores were calculated based on split antigen HLA-A, -B, -DRB1 typing and adjusted to the 0-6 range of HLA mismatches. PIRCHE-II scores correlated strongly with the number of HLA mismatches (Spearman ρ = 0.65, P less then 0.001). In multivariable analyses both parameters were found to be significant predictors of 5-year death-censored graft loss with high prognostic power [hazard ratio (HR) per adjusted PIRCHE-II score = 1.102, per HLA mismatch = 1.095; z-value PIRCHE-II 9.8, HLA 11.2; P less then 0.001 for both]. When PIRCHE-II scores and HLA mismatches were analyzed simultaneously, their predictive power decreased but remained significant (PIRCHE-II P = 0.002; HLA P less then 0.