MicroRNAs (miRNAs) are a family of small, noncoding RNAs that repress gene expression at the post-transcriptional level. Over 700 miRNAs have been identified in the human genome, of which 20% to 30% ...regulate human protein-coding genes. Functional in vitro studies have shown that miRNAs are critical for endothelial cell gene expression and function. miRNAs were found in atherosclerosis, cardiac hypertrophy, arterial hypertension, coronary artery disease, diabetes, and inflammatory diseases. We review the current knowledge about the role of miRNAs in endothelial cells with emphasis on the regulation of cellular senescence, angiogenesis, and vascular inflammation. It has been shown that miR-34a, miR-217, miR-200, miR-146c, and miR-181a are responsible for the regulation of cell stress and proliferation processes. Proangiogenic factors include miR-130a, miR-210, miR-424, miR-17-92, miR-27-b, let-7f, and miR-217, while miR-221 and miR-222 have antiangiogenic properties. Other known miRNAs, including miR-31, miR17-3p, miR-155, miR-221, miR-222, and miR-126, are important factors in the regulation of vascular inflammation. Studies show that miRNA expression analysis can be used in the diagnosis and treatment of various diseases; however, additional research is needed before it is used in routine clinical setting.
Magnetic field is used in therapies designed for patients with rheumatic disorders such as rheumatoid arthritis (RA). The question of selecting adequate treatment parameters to obtain optimal ...therapeutic effects still needs to be answered. The purpose of the study was to assess the influence of magnetic field, depending on its nature, on problems and dysfunctions experienced in upper limbs by patients with RA.
The study group included 14 patients with RA (10 females, 4 males), referred for magnetotherapy to be administered in selected areas of upper limbs. On average, the subjects were 57 years old, and the mean duration of the disorder was 13 years. Magnetotherapy was administered with the use of static or pulsed magnetic field. The patients were examined for the level of disorder, disability level (HAQ-20), severity and duration of morning stiffness, pain intensity (VAS scale), hand volume, swelling and functional capacity. The examinations were carried out before and after a series of ten magnetotherapy treatments.
All the patients reported decreased severity and shorter duration of morning stiffness, reduced level of pain and general disability. There was no statistically significant difference between the groups treated with static and pulsed magnetic field. Statistically significant differences between the groups treated with static and pulsed field were observed in reduced swelling, improved range of motion and muscle strength in the upper limb. The study revealed better effects of pulsed field therapy.
When administered to areas within upper limbs in patients with RA, pulsed magnetic field produced better effects related to the reduction of swelling as well as improving range of motion and muscle strength in the relevant area of the body compared to static field. The findings did not confirm the relationship between the type of magnetic field and its therapeutic effectiveness in reducing pain, morning stiffness and disability level.
All patients with a diagnosis of multiple myeloma (MM) have a preceding, asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance or ...smoldering multiple myeloma (SMM). While most patients with monoclonal gammopathy of undetermined significance have a very small rate of progression, SMM is a widely heterogeneous condition where a fraction of patients will progress to symptomatic MM rather quickly, while others will experience an indolent clinical course. The differentiation between progressive and stable precursor condition thus represents one of the most important unmet clinical needs in the MM community. The ability to identify patients at high-risk of progression before major clonal expansion and onset of end-organ damage would enable strategies for early prevention and perhaps more effective intervention. All proposed criteria to predict the progression of myeloma precursor conditions are built around indirect markers of disease burden and, therefore, are generally able to accurately identify only a small fraction of patients in whom progression to MM is already occurring. Leveraging whole genome and exome sequencing, it has been shown that patients with stable myeloma precursor conditions are characterized by either absence or lower prevalence of distinct genomic events that are detectable in progressive precursor condition years before the progression. In this review, we discuss evolving genomic concepts and tools; and their ability to differentiate myeloma precursor conditions into two distinct entities: one benign (monoclonal gammopathy of benign significance) and another malignant (asymptomatic multiple myeloma).
One of Bergman’s favourite figures was the jester or the clown. When appearing on stage, they gather the whole attention of both audience and other characters. In theatre productions Berg-man used ...three strategies to express his fondness for this figure – he either emphasized jest-ers already existing in the text of the drama, provided other characters with clownish features (both visual and mental), or he even created clown-like figures and added them to the original drama. This was done not only to stress comic aspects, but mainly to expose the psychological complexity of the personalities of these figures. In my article, I analyse all three levels of this phenomenon in productions of Shakespeare, Ibsen and Gombrowicz, trying to find the source of inspiration behind them, as well as a common thread between them
Whole-genome sequencing (WGS) of patients with newly diagnosed multiple myeloma (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e., hotspots) and ...causing recurrent copy-number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as "recurrent SVs." More than half of SVs were not involved in recurrent events. The significance of these "rare SVs" has not been previously examined.
In this study, we utilize 752 WGS and 591 RNA sequencing data from patients with NDMM to determine the role of rare SVs in myeloma pathogenesis.
Ninety-four percent of patients harbored at least one rare SV event. Rare SVs showed an SV class-specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs.
Overall, we demonstrate the association of rare SVs with aberrant gene expression supporting a potential driver role in myeloma pathogenesis.
B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell ...engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
INTRODUCTION: CD19-directed chimeric antigen receptor (CAR-19) T cells have revolutionized clinical outcomes in heavily pretreated patients with aggressive B-cell lymphoma. Notably, emerging evidence ...suggests that the efficacy of CAR-19 therapy extends beyond direct tumor killing and includes its ability to stimulate and guide the host immune system in the fight against tumor cells. To delve deeper into this crucial aspect, our study utilized whole-genome sequencing (WGS) data to explore the impact of neoantigen burden and HLA loss in patients with aggressive large B-cell lymphoma (rrLBCL) who received CAR-19 therapy (WGS; Jain et al. Blood 2022). METHODS: To characterize the importance of genomic immunogenicity in rrLBCL, we conducted a comprehensive analysis of 61 whole-genome sequencing (WGS) and 54 RNA sequencing samples from 54 rrLBCL patients who underwent CAR-19 therapy. Among these samples, 39 were collected at baseline and 15 at relapse, with samples from 7 patients obtained both before and after treatment. Our analytical workflow defined HLA class I mono- or biallelic loss by integrating copy number variants, structural variants, single nucleotide variants, and small insertion-deletion data with allele-specific HLA loss information obtained from LOHHLA software. pVACseq algorithm was used to predict the number of clonal neoantigens in each sample, along with the corresponding HLA allele presenting each of them. RESULTS: HLA class I loss was detected in 38.9% of the patients, with no impact on progression free survival (PFS). Interestingly 7 patients had biallelic loss of HLA-B, and all of them experienced progression within the first year (p=0.03). To expand our analysis, we explored B2M an essential component of HLA class I complexes. B2M was lost in 33.3% of the patients without showing any association with shorter PFS. However, restricting the analysis to patients with B2M biallelic loss (defined as presence of deletions of both alleles, or deletion and mutation with high impact in the structure and function of the B2M protein) 4/4 patients progressed. Overall, all 11 patients with genomic events leading to biallelic loss of HLA class I progressed (p=0.007). Notably, in one patient (CAR_39), biallelic inactivation of HLA class I was not detected at baseline but emerged with the dominant clone at disease progression. HLA class I biallelic loss was associated with genomic drivers previously identified in our study as significantly associated with CAR-19 failure: APOBEC (3/11) and SBS18 (oxygen radical stress; 2/11) mutational signatures, chromothripsis (4/11), RHOA deletions (6/11), and double minutes (4/11). Next, we analyzed the impact of the neoantigen burden corrected for their HLA affinity and allelic status on the outcome of CAR-19 treatment. Patients with high number of neoantigens had shorter PFS (p=0.0095) and were enriched for genomic drivers associated with poor response after CAR-19 (e.g., APOBEC and SBS18). Interestingly, the neoantigen burden had a bimodal distribution across patients that progressed with two distinct groups: one with high neoantigen burden, biallelic loss of HLA, and high genomic complexity and the other with low genomic complexity and low neoantigen burden. Restricting the analysis to patients with retained HLA and low genomic complexity, high neoantigen burden associated with prolonged and favorable response to CAR-T therapy (p=0.04). CONCLUSION: This study offers evidence that there is a critical relationship between CAR-19 efficacy, LBCL immunogenicity, and the endogenous immune response.
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