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Keyword Index for Volume 93

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… colorectal adenomas 954 colorectal cancer 1, 399, 510, 744, 799, 896, 1230, 1236 comorbidities 1098 comparison 552 contrast agent 131 C-reactive protein 639 CRM 529 CT antigen 458 cutaneous melanoma 597 CXCR4 924 cyclin A 515 cyclin D1, D2, D3 338 cyclooxygenase-2 954 cytarabine 1388 cytidine …

RNA метилтрансферазы METTL8 устанавливает m3C32 в митохондриальном tRNASThr/Ser (UCN) для оптимизации структуры trNA и митохондриального перевода.

Модифицированные нуклеотиды в tRNA являются важными определяющими факторами сворачивания, структуры и функции. Здесь мы идентифицируем METTL8 как митохондриальный белок и активный РНК метилтрансферазы, ответственный за установку m3C32 в митохондриале человека (mt-)tRNAThr и mt-tRNAser (UCN). METTL8 имеет перекрестные связи с антикодоновой стволовой петлей (ASL) многих мт-тРНК в клетках, в связи с чем возникает вопрос о том, каким образом достигается целевая специфичность метилирования. Расчленение элементов распознавания mt-tRNA выявило наличие U34G35 и t6A37/(ms2)i6A37, которые одновременно п

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… Methylation of N3 of cytidine (3-methylcytidine; m 3 C) is present at position 32 of eukaryotic, cytoplasmic tRNAs Thr and tRNAs Ser in species ranging from yeast to humans and has also been identified in mitochondrial (mt-)tRNA Thr/Ser(UCN) in mammals 29 – 36 . … Among the mt-tRNAs, eight have a cytidine in position 32 and a modified adenosine at position 37, yet only mt-tRNA Thr and mt-tRNA Ser(UCN) are reported to have m 3 C 32 (Supplementary Fig. 5 ). …

Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives.

Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy

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… Hypomethylating Agents (HMAs) HMAs are acting as pyrimidine analogs of the nucleoside cytidine. Its incorporation into DNA leads to an irreversible link between the cytidine analogue and the DNA methyltransferase (DNMT), which causes inhibition of the latter. … Cytosine derivatives underlie a natural degradation mediated by cytidine deaminases (CDA). The expression level of CDA is known to be a predictor for HMA response and thus representing a potential target to improve sensitivity to HMAs [ 80 ]. …

First-in-Human Phase I Study of MBC-11, a Novel Bone-Targeted Cytarabine-Etidronate Conjugate in Patients with Cancer-Induced Bone Disease.

Lessons learnedResults are consistent with MBC-11 targeting and treating cancer-induced bone lesions by concentrating cytarabine and etidronate at the site of disease.MBC-11 was well tolerated, with an maximum tolerated dose of 5 mg/kg per day and myelosuppression as the principal toxicity.Treatment significantly reduced cancer cell activity in over half of bone lesions detected at baseline.MBC-11 pharmacokinetic and pharmacodynamic parameters are consistent with the novel drug design goals, and encouraging results warrant further clinical development.BackgroundMBC-11 is a first-in-class conju

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… Bisphosphonate derivatives of nucleoside antimetabolites: Hydrolytic stability and hydroxyapatite adsorption of 5'‐beta, gamma‐methylene and 5'‐beta, gamma‐(1‐hydroxyethylidene) triphosphates of 5‐fluorouridine and ara‐cytidine. J Org Chem 2018;73:4123–4130. 2. …

B-cells in pulmonary arterial hypertension: friend, foe or bystander?

There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH). As immunity has been involved in the development and progression of vascular lesions in PAH, we review the potential contribution of B-cells in its pathogenesis and evaluate the relevance of B-cell-targeted therapies. Circulating B-cell homeostasis is altered in PAH patients, with total B-cell lymphopenia, abnormal subset distribution (expansion of naïve and antibody-secreting cells, reduction of memory B-cells) and chronic acti

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… Dark zone B-cells, referred to as centroblasts, undergo a process called somatic hypermutation (SHM) (mutations in the Ag-binding region of the BCR, that increase its affinity for the Ag), mediated by an enzyme called activation-induced (cytidine) deaminase (AID), during which they stop expressing their … B-cell activation in TLOs leads to a germinal-centre reaction, as suggested by the presence of B-cell lymphoma (Bcl)2 − Bcl6 + Ki67 + B-cells (characteristic of germinal-centre B-cells) within follicles, the strong over-expression of activation-induced cytidine deaminase (AID) (supporting the occurrence …

Modulating epigenetic modifications for cancer therapy (Review).

Cancer is a global public health concern. Alterations in epigenetic processes are among the earliest genomic aberrations occurring during cancer development and are closely related to progression. Unlike genetic mutations, aberrations in epigenetic processes are reversible, which opens the possibility for novel pharmacological treatments. Non‑coding RNAs (ncRNAs) represent an essential epigenetic mechanism, and emerging evidence links ncRNAs to carcinogenesis. Epigenetic drugs (epidrugs) are a group of promising target therapies for cancer treatment acting as coadjuvants to reverse drug resist

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… Zebularine In the early 1990s, second-generation nucleoside analogs were synthesized, such as zebularine [1-(β-D-ribofuranosyl)-2(1H)-pyrimidinone], a cytidine analog that lacks the amino (N) group at position four of the pyrimidine ring ( 79 ). … It has high stability under physiological conditions and inhibits DNA methylation through its action on DNMTs and cytidine deaminase, an enzyme responsible for resistance to nucleoside DNA methylation analogs ( 80 ). …

Definitions, Biology, and Current Therapeutic Landscape of Myelodysplastic/Myeloproliferative Neoplasms.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022 International Consensus Classification (ICC), MDS/MPN consists of clonal monocytosis of undetermined significance (CMUS), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with SF3B1 mutation (MDS/MPN-T-SF3B1), MDS/MPN with ring sideroblasts and thrombocytosis not otherwise specified (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS. These disorders exhibit a diverse range of genetic alterations involving

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… HMA must be given IV due to cytidine deaminase, an enzyme that breaks down DAC and AZA in the small intestine and liver, reducing HMA effectiveness when taken orally. … Cedazuridine inhibits cytidine deaminase, preventing DAC degradation and allowing for efficient delivery when co-taken orally. …

What Is New in the Treatment of Smoldering Multiple Myeloma?

Smoldering multiple myeloma (SMM), an asymptomatic plasma cell neoplasm, is currently diagnosed according to the updated IMWG criteria, which reflect an intermediate tumor mass between monoclonal gammopathy of undetermined significance (MGUS) and active MM. However, SMM is a heterogeneous entity and individual case may go from an "MGUS-like" behavior to "early MM" with rapid transformation into symptomatic disease. This wide range of clinical outcomes poses challenges for prognostication and management of individual patients. However, initial studies showed a benefit in terms of progression or

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… Initiating lesions arise from the activity of the DNA activation-induced cytidine deaminase (AID) within the germinal center, while late mutations associated with progression to MM arise from the aberrant activity of the APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family of cytidine …

Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression.

The prognosis of patients with metastatic breast cancer remains poor, and thus novel therapeutic approaches are needed. Capecitabine, which is commonly used for metastatic breast cancer in different settings, is an inactive prodrug that takes advantage of elevated levels of thymidine phosphorylase (TP), a key enzyme that is required for its conversion to 5-fluororacil, in tumors. We demonstrated that histone deacetylase inhibitors (HDACi), including low anticonvulsant dosage of VPA, induced the dose- and time-dependent up-regulation of TP transcript and protein expression in breast cancer cell

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… Abbreviation: CE, carboxylesterase; 5-DFCR, 5′-deoxy-5-fluorocytidine; CyD, cytidine deaminase; 5-DFUR, 5′-deoxy-5-fluorouridine; TP, thymidine phosphorylase; 5-FU, 5-fluorouracil; OPRT, orotate phosphoribosyl transferase; FUMP, 5-fluorouridine monophosphate; FUDP, 5-fluorouridinediphosphate; RR, ribonucleotide … deoxyuridine; TK, thymidine kinase; F-dUDP, 5-Fluoro-2′-deoxyuridine diphosphate; F-dUMP, 5-fluoro-2′-deoxyuridine monophosphate; dUMP, 2′-deoxyuridine monophosphate; TS, thymidylate synthase; F-dUTP, 5-Fluoro-2′-deoxyuridine triphosphate; NDK, nucleoside diphosphate kinase; UMP-CMPK, urdine monophosphate-cytidine …

Nucleotide Metabolism in Health and Disease.

Nucleotide metabolism is a fundamental biochemical process, providing the building blocks for DNA and RNA synthesis while driving critical cellular functions like energy transfer, signal transduction, and coenzyme synthesis. The precise regulation of nucleotide de novo synthesis, salvage, and degradation pathways is imperative for maintaining genomic stability and tissue homeostasis. Aberrations in these networks are increasingly recognized as primary drivers in various pathologies; notably, cancer cells exploit metabolic-functional reprogramming to enable rapid proliferation and therapeutic r

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… Cytidine nucleotides and thymidine nucleotides can be derived from UMP [ 56 ]. … NDP Kinase Cytidine and uridine analog monophosphates are phosphorylated by UMP/CMP kinase [ 280 ], a protein whose synthesis is directed by the CMPK1 gene [ 281 , 282 ]. …

Precision in Action: The Role of Clustered Regularly Interspaced Short Palindromic Repeats/Cas in Gene Therapies.

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated enzyme-CAS holds great promise for treating many uncured human diseases and illnesses by precisely correcting harmful point mutations and disrupting disease-causing genes. The recent Food and Drug Association (FDA) approval of the first CRISPR-based gene therapy for sickle cell anemia marks the beginning of a new era in gene editing. However, delivering CRISPR specifically into diseased cells in vivo is a significant challenge and an area of intense research. The identification of new CRISPR/Cas variants, particularly

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… A recent study used an rAAV vector and CRISPR with a cytidine base editor to correct PAH mutation. About 63% of the mRNA correction rate was achieved, and a normal phenylalanine level was restored post-gene therapy in these mice [ 271 ]. … Base editing with a Cpf1-cytidine deaminase fusion Nat. Biotechnol. 2018 36 324 327 10.1038/nbt.4102 29553573 38. Gaudelli N.M. Komor A.C. Rees H.A. Packer M.S. Badran A.H. Bryson D.I. Liu D.R. …

Current advances of CRISPR-Cas technology in cell therapy.

CRISPR-Cas is a versatile genome editing technology that has been broadly applied in both basic research and translation medicine. Ever since its discovery, the bacterial derived endonucleases have been engineered to a collection of robust genome-editing tools for introducing frameshift mutations or base conversions at site-specific loci. Since the initiation of first-in-human trial in 2016, CRISPR-Cas has been tested in 57 cell therapy trials, 38 of which focusing on engineered CAR-T cells and TCR-T cells for cancer malignancies, 15 trials of engineered hematopoietic stem cells treating hemog

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… Improving cytidine and adenine base editors by expression optimization and ancestral reconstruction. Nat. Biotechnol. 2018;36:843–846. doi: 10.1038/nbt.4172. Koenig M., Hoffman E.P., Bertelson C.J., Monaco A.P., Feener C., Kunkel L.M. …

Epigenome-Driven Strategies for Personalized Cancer Immunotherapy.

Fighting cancer remains one of the greatest challenges for science in the 21st century. Advances in immunotherapy against different types of cancer have greatly contributed to the treatment, remission, and cure of patients. In this context, knowledge of epigenetic phenomena, their relationship with tumor cells and how the immune system can be epigenetically modulated represent some of the greatest advances in the development of anticancer therapies. Epigenetics is a rapidly growing field that studies how environmental factors can affect gene expression without altering DNA sequence. Epigenomic

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… These inhibitors are cytidine nucleoside analogues capable of binding specifically to DNMT DNA proteins, irreversibly sequestering them. … induction of inflammation by increased expression of chemokines or a combination of two or more of these factors. 98 , 99 Methylation of DNMTis can lead to cycles of recurrent Cancer-testis antigens (CTAs) biosynthesis in many different solid tumors, and the use of 5-azacytidine, the chemical analog of cytidine …

DNA Damaging Drugs

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Transcriptomic analysis of mRNAs in human whole blood identified age-specific changes in healthy individuals.

Older age is one of the most important shared risk factors for multiple chronic diseases, increasing the medical burden to contemporary societies. Current research focuses on identifying aging biomarkers to predict aging trajectories and developing interventions aimed at preventing and delaying the progression of multimorbidity with aging. Here, a transcriptomic changes analysis of whole blood genes with age was conducted. The age-related whole blood gene-expression profiling datasets were downloaded from the Gene Expression Omnibus (GEO) database. We screened the differentially expressed gene

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… Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution. Nat Commun. 2015;6:8866. [23] Zhao A, Wu F, Wang Y, et al. …

Molecular Targeting and Rational Chemotherapy in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a molecularly complex disease with multiple aberrant genetic pathways involved in its pathogenesis. Approximately one-third to one-half of patients with AML would relapse, and no standard therapy is established for relapsing and/or refractory AML (RR-AML) yet. It is unlikely that blockage of only one specific pathway will lead to prolonged remissions and cures in all fractions of the AML patients population. Nowadays, novel therapeutic agents with rational combination are being recognized which improve the cure rate for relapsed AML. These drugs and their metabo

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… Single Agent Treatment** | Clof, Cycl, Etop Treatment CR | 1/8 (13%) | 3/3 (100%) PR** | 2/8 (25%) | – CR + CRp | 3/8 (38%) | 3/3 (100%) Table 2 FDA approved purine /pyrimidine anti-metabolites used in the combination therapy of AML 6 Drug Name/Structure | Drug Name/Structure 5-Aza-cytidine | 5-Aza- … repair. 32 In transformed cells, the level of a biomarker of DBSs in DNA, phosphorylated histone variant γH2AX, increases with continued culture with vorinostat whereas normal cells repair the DSBs despite continued exposure to vorinostat. 29 On the other side, the nucleotide antimetabolites 5-aza-cytidine …

Unlocking the potential: advancements and applications of gene therapy in severe disorders.

INTRODUCTION: Several severe disorders, such as inherited diseases (e.g. cystic fibrosis and beta thalassemia), genetic diseases (e.g. malignant tumors and diabetes), and infectious diseases (e.g. HIV) are pose significant challenges to human health. BACKGROUND: Over the past few decades, researchers have been working on gene therapies, and currently, terrible dreams have come true. To date, the Food and Drug Administration (FDA) has approved multiple gene therapies such as Kynamro for familial hypercholesterolaemia, Exondys51 for duchenne muscular dystrophy, Spinraza for spinal muscular atro

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… Target-AID (activation-induced cytidine deaminase) is developed by nCas9, Petromyzon marinus cytidine deaminase 1 (pmCDA1), respectively [ 48 ]. …

Pharmacological Strategies for Mitigating Cytarabine-Induced Multi-Organ Toxicity: A Scoping Review on Mechanisms, Efficacy and Clinical Implications.

BACKGROUND: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML … ing (apraglutide, BADGE, plerixafor, short-chain fatty acids, β-glucan), molecular antagonism (deoxycytidine, dCMP), and immunomodulation (lienal peptide, IL-1β, AHCC). CONCLUSIONS: This scoping review provides the first systematic cartography of pharmacological mitigation strategies for cytarabine-induced multi-organ toxicity. Five mechanistic pathways c …

HIV-Associated Lymphomas: Updates from Pathogenesis to Treatment Strategies.

HIV-associated lymphoma (HAL) is an aggressive malignancy directly linked to HIV infection and accounts for more than 30% of cancer-related deaths in people living with HIV (PLWH). HAL subtypes, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), primary effusion lymphoma (PEL), and plasmablastic lymphoma (PBL), exhibit five to ten times higher incidence rates and distinct molecular profiles compared to HIV-negative lymphomas. Pathogenesis involves HIV-driven CD4+ T-cell depletion, chronic B-cell activation, and oncogenic viral coinfection. First-line therapy combines antir

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… Nef elevates activation-induced cytidine deaminase (AID) and MYC, further promoting genomic instability [ 38 ]. In contrast, chronic HIV infection fosters T-cell malignancy via the Vpr-VprBP-Plk4 complex and integration of HIV-1 provirus into key regulatory genes [ 39 ]. … HIV Nef enhances the expression of oncogenic c-MYC and activation-induced cytidine deaminase in Burkitt lymphoma cells, promoting genomic instability. Infect. Agent. Cancer. 2020;15(1):54. doi: 10.1186/s13027-020-00320-9. 39. Park J.E., Kim T.S., Zeng Y., et al. …

IL-22 способствует возникновению хронической гаммагерпесвирусной инфекции, поддерживая реакцию микробного центра.

Гаммагерпесвирусы, включая вирус Эпштейн-Барр (EBV) и герпесвирус, связанный с Карпози (KSHV), создают скрытые инфекции на протяжении всей жизни, которые способствуют множественным заболеваниям раком и множественным склерозом. Эти вирусы колонизируют наивные клетки B и приводят в действие мощный, поликлонный герминальный центр, чтобы расширить латентный вирусный резервуар и установить пожизненную инфекцию в клетках памяти B. Несмотря на клиническое бремя этих вирусов, факторы, способствующие хронической инфекции, по-прежнему плохо определены. " Interleukin-22 " (IL-22) является крити

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… Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells . … Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas . Nature . 2002 ; 415 ( 6873 ): 802 – 6 . doi: 10.1038/nature714 11823785 15 Küppers R . B cells under influence: transformation of B cells by Epstein-Barr virus . …