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VEXAS Syndrome: A Comprehensive Review of Current Therapeutic Strategies and Emerging Treatments.

VEXAS syndrome is a recently identified autoinflammatory disorder resulting from somatic mutations in the UBA1 gene, leading to a complex spectrum of severe inflammatory and hematologic manifestations. The absence of established treatment guidelines and the variability in clinical presentation make its management particularly challenging. Current therapeutic approaches are often based on limited evidence, and their effectiveness remains inconsistent. This review seeks to consolidate the existing knowledge on therapeutic strategies for VEXAS syndrome, offering a critical evaluation of their eff

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… Azacytidine Azacytidine is a pyrimidine nucleoside analog of cytidine, widely used to treat various hematological disorders, including MDS, which is strongly associated with VEXAS syndrome. …

Молекулярная основа для человеческой митохондриальной модификации tRNA m3C с помощью альтернативной разбрызгивания METTL8.

METTL8 недавно был определен как катализатор метилпереносазы 3-methylcytidine Биогенез на месте 32 (м3С32) митохондриальных tRNA. METTL8 также потенциально участвует в мRNA метилации и R-loop Biogenesis. Как METTL8 играет многообразную роль в разных камерах, и митохондриальное образование митохондриала tRNA m3C остается неясным. Здесь мы обнаружили, что альтернативное скрещивание mRNA вызвало несколько изоформ METTL8. One (изоформ)METTL8-Iso1) был направлен на митохондрию через N-терминальную предпоследнюю последовательность, в то время как другой one (В тыс.METTL8-Iso4) в основном локализован…

Стратегия выбора субстрата, взаимно исключающаяся, у человека m3C RNA трансферазы METTL2A и METTL6.

tRNAs содержат наиболее разнообразные посттранскрипционные модификации. 3-метилцитидин (m3C) широко распределяется на позиции C32 (m3C32) у эукариотических tRNAThr и tRNASer. m3C32 модифицируется единственным метилтрансферазой Trm140 у дрожжей-попыток; однако для его биогенеза участвуют два (Trm140 и Trm141 у деления дрожжей) или три энзима (METTL2A, METTL2B и METTL6 у млекопитающих). До сих пор неизвестно обоснование существования нескольких метилтрансфераз m3C32 и их механизм дифференциации по субстрату. Здесь мы обнаружили, что оба METTL2A и METTL2B выражены в живых организмах. Мы выделили

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tRNAs harbor the most diverse posttranscriptional modifications. The 3-methylcytidine (m3C) is widely distributed at position C32 (m3C32) of eukaryotic tRNAThr and tRNASer species. m3C32 is decorated by the single methyltransferase Trm140 in budding yeasts; however, two (Trm140 and Trm141 in fission yeasts) or three enzymes (METTL2A, METTL2B and METTL6 in ma…

Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy.

In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling

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… Moreover, using low concentrations of ALM resulted in an enhanced effect of Everolimus, an inhibitor of mTOR already used in anti-cancer therapy. 68 The combination of ALM and Everolimus enables a lower drug dose and more efficient therapy for solid tumor patients. 68 Zebularine, the analog of cytidine …

Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer.

Metastatic bone cancer occurs in every type of cancer but is prevalent in lung, breast, and prostate cancers. These metastases can cause extensive morbidity, including a range of skeletal-related events, often painful and linked with substantial hospital resource usage. The treatment used is a combination of chemotherapy and surgery. However, anticancer drugs are still limited due to severe side effects, drug resistance, poor blood supply, and non-specific drug uptake, necessitating high toxic doses. Bisphosphonates are the main class of drugs utilized to inhibit metastatic bone cancer. It is

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… N4-[Alkyl-(hydroxyphosphono) phospho-nate]-cytidine—New drugs covalently linking antimetabolites (5-FdU, araU or AZT) with bone-targeting bisphosphonates (alendronate or pamidronate) Bioorg. Med. Chem. 2011;19:3520–3526. doi: 10.1016/j.bmc.2011.04.015. 119. …

Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs.

Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still succumbs to chemoresistant disease. Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA fragments and act as key players in the regulation of both physiologic and pathologic gene expression profiles. Aberrant expression of various non-coding RNAs proved to be of seminal im

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… While LDAC served as the mainstay of AML LITR for a long time, the recent introduction of HMA treatments remarked a further significant development in this area [ 1 , 8 ], with the cytidine analogues azacitidine (5-azacytidine) and decitabine (5-aza-2′-deoxycytidine) representing the currently best studied …

Epigenetics-targeted drugs: current paradigms and future challenges.

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifyin

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… This cytidine deaminase enzyme inhibitor enhances decitabine exposure after oral administration. … It is an antinucleotide molecule that resists degradation by cytidine deaminase. 275 Research primarily focuses on its application against various malignant tumors. …

Genome-edited allogeneic CAR-T cells: the next generation of cancer immunotherapies.

Chimeric Antigen Receptor T (CAR-T) cell therapy has revolutionized cancer immunotherapy, particularly in hematological malignancies. However, the clinical application of autologous CAR-T cells faces significant high cost and manufacturing challenges. Universal allogeneic CAR-T cells, derived from healthy donors, represent a promising solution to these obstacles. These "off-the-shelf" therapies aim to reduce the complexity and cost of CAR-T production. Despite exciting advancements in genome-editing technologies and promising clinical trial data, significant challenges remain, including graft-

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… Base editors contain a Nickase Cas9 (nCas9) variant, tethered to cytidine and adenosine deaminase for catalyzing highly targeted C→T or A→G base conversion, and introduces premature STOP codons or interferes with splicing sites to cause gene disruption without creating DSBs. ( I ) Prime editing system … Base editing CRISPR-guided cytidine or adenosine deamination can mediate a highly precise C→T or A→G base conversion, respectively [ 97 ]. …

Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease.

We present an overview of clinical trials involving gene editing using clustered interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), or zinc finger nucleases (ZFNs) and discuss the underlying mechanisms. In cancer immunotherapy, gene editing is applied ex vivo in T cells, transgenic T cell receptor (tTCR)-T cells, or chimeric antigen receptor (CAR)-T cells to improve adoptive cell therapy for multiple cancer types. This involves knockouts of immune checkpoint regulators such as PD-1, components of the endo

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… without involvement of HDR; 27 microhomology-mediated end joining (MMEJ)-dependent knockin, which is based on the presence of short stretches of homology that are utilized by the MMEJ DNA repair pathway; 28 base editing, 29 a mismatch repair- or base excision repair-dependent pathway in which a natural cytidine … or adenosine deaminase (ADA) is coupled to a catalytically dead Cas9 (dCas9) to convert cytidine to uridine (which is replicated as thymidine), or to convert adenine to inosine, which is replicated as guanine; and prime editing, 30 in which a Cas9 nicking variant is used that introduces single stranded …

Chronotherapy in Hematological Malignancies: Evaluating the Rationale and Evidence.

Hematological malignancies remain one of the leading causes of morbidity and mortality despite advances in targeted therapies, immunotherapy, and stem cell transplantation. Emerging evidence indicates that treatment efficacy and toxicity depend not only on the choice of therapy but also on its timing relative to the patient's internal circadian rhythm. The circadian clock orchestrates fundamental processes in hematopoiesis and immunity, such as stem-cell proliferation, leukocyte trafficking, DNA repair, and drug metabolism, while its disruption promotes malignant transformation, therapeutic re

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… Conversely, nocturnal dosing of oxaliplatin and irinotecan, agents metabolized by rhythmic hepatic carboxylesterases and cytidine deaminase, can minimize toxicity while maintaining efficacy [ 57 , 58 ]. …

Communication between gut microbiota-derived metabolites and the tumor microenvironment.

The gut microbiota has been increasingly recognized as a critical player in maintaining human health and influencing disease development. The tumor microenvironment (TME) is pivotal in tumor development and progression, comprising immune cells, stromal elements, extracellular matrix components, and cytokines. Recent studies have highlighted the promising potential of gut microbiota-derived metabolites (e.g., short-chain fatty acids, bile acids, polyamines, and tryptophan derivatives) to reshape the TME in various ways, generating significant interest for the development of novel therapeutic st

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… Low levels of butyrate and propionate have been shown to moderately enhance class-switch DNA recombination in B cells whereas higher levels can inhibit activation-induced cytidine deaminase and Blimp1 expression, ultimately suppressing class-switch DNA recombination (CSR) and plasma cell differentiation …

Autoimmune Diseases and Plasma Cells Dyscrasias: Pathogenetic, Molecular and Prognostic Correlations.

Multiple myeloma and monoclonal gammopathy of undetermined significance are plasma cell dyscrasias characterized by monoclonal proliferation of pathological plasma cells with uncontrolled production of immunoglobulins. Autoimmune pathologies are conditions in which T and B lymphocytes develop a tendency to activate towards self-antigens in the absence of exogenous triggers. The aim of our review is to show the possible correlations between the two pathological aspects. Molecular studies have shown how different cytokines that either cause inflammation or control the immune system play a part i

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… Numerous additional genes are also repressed by BLIMP-1, such as MHC class II transactivator (CIITA), which is necessary for MHC class II expression, and activation-induced cytidine deaminase (AID), which is necessary for SHM and isotype class switching. …

Targeted CD7 CAR T-cells for treatment of T-Lymphocyte leukemia and lymphoma and acute myeloid leukemia: recent advances.

The high expression of CD7 targets in T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoma has attracted considerable attention from researchers. However, because CD7 chimeric antigen receptor (CAR) T-cells undergo fratricide, CD7 CAR T-cells develop an exhaustion phenotype that impairs the effect of CAR T-cells. There have been significant breakthroughs in CD7-targeted CAR T-cell therapy in the past few years. The advent of gene editing, protein blockers, and other approaches has effectively overcome the adverse effects of conventional methods of CD7 CAR T-cells. This review, in conjunc

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… Cytosine base editors (CBEs) are made by fusing cytidine deaminase into Cas9 endonuclease (nicase) or TALEN sequence with uracil glycosylase inhibitory domain (UGI) to convert C • G base pairs to T • A base pairs at specific locations in the genome ( 57 ). …

The Role of Long Non-Coding RNA and microRNA Networks in Hepatocellular Carcinoma and Its Tumor Microenvironment.

Hepatocellular carcinoma (HCC) is a common liver malignancy with high morbidity and poor prognosis. Long non-coding RNAs (lncRNAs) are involved in crucial biological processes of tumorigenesis and progression, and play four major regulatory roles, namely signal, decoy, guide, and scaffold, to regulate gene expression. Through these processes, lncRNAs can target microRNAs (miRNAs) to form lncRNA and miRNA networks, which regulate cancer cell proliferation, metastasis, drug resistance, and the tumor microenvironment. Here, we summarize the multifaceted functions of lncRNA and miRNA networks in t

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… Hypoxia-induced lncRNA NEAT1 [ 133 ] and EIF3J antisense RNA 1 (EIF3J-AS1) [ 134 ] promote HCC proliferation by regulating the miR-199a-3p/ uridine-cytidine kinase 2 (UCK2) and miR-122-5p/ catenin delta 2 (CTNND2) axis, respectively. …

From Bench to Bedside and Beyond: Therapeutic Scenario in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous group of clonal disorders characterized by abnormal proliferation of undifferentiated myeloid progenitors, impaired hematopoiesis, and variable response to therapy. To date, only about 30% of adult patients with AML become long-term survivors and relapse and/or disease refractoriness are the major cause of treatment failure. Thus, this is an urgent unmet clinical need and new drugs are envisaged in order to ameliorate disease survival outcomes. Here, we review the latest therapeutic approaches (investigational and approved agents) for AML treatme

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… The next-generation DNA hypomethylating agent guadecitabine (SGI-110) was originally produced to resist degradation inferred by cytidine deaminase and extend the exposure of tumor cells to DAC. This drug has been shown to promote tumor associated antigens and sensitize tumor cells to immunotherapy. …

Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are a diverse group of chronic hematological disorders that involve unregulated clonal proliferation of white blood cells. Sevearl of them are associated with mutations in receptor tyrosine kinases or cytokine receptor associated tyrosine kinases rendering them independent of cytokine-mediated regulation. Classically they have been broadly divided into BCR-ABL1 fusion + ve (Ph + ve) or -ve (Ph-ve) MPNs. Identification of BCR-ABL1 tyrosine kinase as a driver of chronic myeloid leukemia (CML) and successful application of small molecule inhibitors of the tyrosi

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… 24 th January 2015 Compounds | Target/mechanism | National Clinical Trial Identifier | Phase | Condition | Status Decitabine | Anti-metabolite chemotherapeutic, DNA demethylation | NCT02076191 | I/II | Accelerated or blast phase MPN | Recruiting Azacitidine (Vidaza) | Chemical analogue of nucleoside cytidine …

Chimeric Antigen Receptor T-Cell Revolution Remodeling Immunity to Conquer Autoimmune Disease.

Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking technology in tumor immunotherapy, has demonstrated unprecedented potential in the field of autoimmune diseases in recent years. This article provides a systematic review of the developmental trajectory and core concepts of CAR-T-cell therapy in autoimmune diseases, emphasizing its conceptual evolution from traditional "killing" strategies to "precision immune remodeling". Leveraging multitarget approaches (e.g., CD19 and B-cell maturation antigen) and chimeric autoantigen receptor technology, it achieves efficient elimination

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… Additionally, epigenetic abnormalities (e.g., DNA methylation) lead to B-cell hyperactivation, and abnormal expansion of subsets such as marginal-zone B cells/GC B cells contributes to pathology; aberrant activation-induced cytidine deaminase (AID) expression in GC B cells affects BCR diversity and autoreactive …

Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance.

Recent insight in the genomic landscape of newly diagnosed multiple myeloma (NDMM) and its precursor conditions, monoclonal gammopathy of uncertain significance (MGUS), and smoldering myeloma have allowed the identification of patients with precursor conditions with a high risk of progression. These cases with "progressor" MGUS/SMM have a higher average mutation burden, have higher rates of mutations in specific genes such as MAPK, DNA repair, MYC, DIS3, and are enriched for specific mutational signatures when compared to non-progressors and are comparable to those found in NDMM. The highly pr

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… These include evidence of activity of the enzyme activation-induced cytidine deaminase (AID) across immunoglobulin locus (known as canonical AID, c-AID) and in non-immunoglobulin areas (known as non-canonical AID, nc-AID), APOBEC, “clock-like” signatures (related to constant mutation over time ( 31 ) …

Immune defects in the risk of infection and response to vaccination in monoclonal gammopathy of undetermined significance and multiple myeloma.

The plasma cell proliferative disorders monoclonal gammopathy of undetermined significance (MGUS) and malignant multiple myeloma (MM) are characterized by an accumulation of transformed clonal plasma cells in the bone marrow and production of monoclonal immunoglobulin. They typically affect an older population, with median age of diagnosis of approximately 70 years. In both disorders, there is an increased risk of infection due to the immunosuppressive effects of disease and conjointly of therapy in MM, and response to vaccination to counter infection is compromised. The underlying factors in

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… In mechanistic insights, key observations suggests an intrinsic defect in deletional class switch recombination (CSR) due to decreased expression of activation-induced cytidine deaminase (AID) with age ( 43 , 52 ). AID is a pre-requisite for both TD and TI B-cell responses. …

Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis.

Tumor aggressiveness and progression is highly dependent on the process of metastasis, regulated by the coordinated interplay of genetic and epigenetic mechanisms. Metastasis involves several steps of epithelial to mesenchymal transition (EMT), anoikis resistance, intra- and extravasation, and new tissue colonization. EMT is considered as the most critical process allowing cancer cells to switch their epithelial characteristics and acquire mesenchymal properties. Emerging evidence demonstrates that epigenetics mechanisms, DNA methylation, histone modifications, and non-coding RNAs participate

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… Cellular differentiation, cytidine analogs and DNA methylation Cell 1980 20 85 93 10.1016/0092-8674(80)90237-8 6156004 165. Jones P.A. Taylor S.M. Wilson V. DNA modification, differentiation, and transformation J. Exp. Zool. 1983 228 287 295 10.1002/jez.1402280212 6198436 166. Tan E.-J. Kahata K. …