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Mutation Processes in 293-Based Clones Overexpressing the DNA Cytosine Deaminase APOBEC3B.

Molecular, cellular, and clinical studies have combined to demonstrate a contribution from the DNA cytosine deaminase APOBEC3B (A3B) to the overall mutation load in breast, head/neck, lung, bladder, cervical, ovarian, and other cancer types. However, the complete landscape of mutations attributable to this enzyme has yet to be determined in a controlled human cell system. We report a conditional and isogenic system for A3B induction, genomic DNA deamination, and mutagenesis. Human 293-derived cells were engineered to express doxycycline-inducible A3B-eGFP or eGFP constructs. Cells were subject

An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study.

BACKGROUND: Decitabine, a DNA methyltransferase 1 inhibitor or DNA hypomethylating compound, is not readily orally bioavailable because of rapid clearance by cytidine deaminase (CDA) in the gut and liver. This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases decitabine bioavailability for the treatment of myelodysplastic syndromes. METHODS: In this phase 1 study, we enrolled patients aged 18 years or older with myelodysplastic syndromes or chronic myelomonoc…

Low-molecular weight compounds in human seminal plasma as potential biomarkers of male infertility.

STUDY QUESTION: Is the determination of antioxidants, oxidative/nitrosative stress-related compounds, purines, pyrimidines and energy-relate … spermiogram anomalies differed in some biomarkers (ascorbic acid, all-trans retinol, α-tocopherol, cytidine, uridine, guanine). These differences were reinforced by distribution frequencies and posterior probability curves of the Biomarker Score in the three groups. LIMITATIONS, REASONS FOR CAUTION: Results were obtained in relatively limited number of h …

DNA methylation inhibition in myeloma: Experience from a phase 1b study of low-dose continuous azacitidine in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma.

The DNA methyltransferase inhibitor azacytidine (aza) may reactivate pathways associated with plasma cell differentiation, cell cycle control, apoptosis, and immune recognition and thereby restore sensitivity to lenalidomide (len) and dexamethasone (dex) in relapsed and/or refractory multiple myeloma (RRMM). We aimed to develop an aza regimen that reaches epigenetically active levels 8 times in 28 days with less bone marrow toxicity than the myeloid malignancy standard of 7 consecutive doses to enable safe combination with len. Aza was escalated from 30 mg/m2 once a week up to a predefined max…

A calcium channel in human submandibular duct cell line, HSG cells, not regulated by P2U purinergic receptor-mediated intracellular calcium mobilization.

Signal transduction via P2 purinergic receptors was investigated in HSG cells, a continuous cell line originally derived from an irradiated human salivary gland. Ligand specificity for nucleotide receptors in HSG cells was investigated with various nucleotides and their analogues. Inositol 1,4,5-trisphosphate (IP3) production was significantly increased by ATP, UTP and ATP gamma S. The ligand specificity of this effect agreed well with that of the P2U purinergic receptor. On the other hand, 45Ca2+ influx was stimulated by ATP, UTP > ATP gamma S, ADP, UDP > ADP beta S > AMPPNP, GTP, TTP > CTP,

Simultaneous integrated boost-intensity modulated radiation therapy with concomitant capecitabine and mitomycin C for locally advanced anal carcinoma: a phase 1 study.

PURPOSE: Newer radiation techniques, and the application of continuous 5-FU exposure during radiation therapy using oral capecitabine may improve the treatment of anal cancer. This phase 1, dose-finding study assessed the feasibility and efficacy of simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with concomitant capecitabine and mitomycin C in locally advanced anal cancer, including pharmacokinetic and pharmacogenetic analyses. METHODS AND MATERIALS: Patients with locally advanced anal carcinoma were treated with SIB-IMRT in 33 daily fractions of 1.8 Gy to the

Adverse Events Associated with Antivirals for COVID-19: An Analysis Based on FDA Adverse Event Reporting System (FAERS).

BACKGROUND: The COVID-19 pandemic has called for the rapid development and use of antiviral drugs to effectively control the disease. Nirmatrelvir/Ritonavir (Paxlovid), Molnupiravir, and Remdesivir have been pivotal in therapeutic approaches, although they raise concerns regarding adverse drug reactions (ADRs). OBJECTIVE: This study aimed to thoroughly assess the ADRs associated with these drugs by utilizing the Adverse Event Reporting System (FAERS) database of the Food and Drug Administration (FDA). METHODS: ADR reports for Paxlovid, Molnupiravir, and Remdesivir throughout the period of Ja

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.

Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Here, we show that the ribonucleoside analog β-d-N4-hydroxycytidine (NHC; EIDD-1931) has broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs, as well as increased potency against a CoV bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administ…

Effects of extracts and isolated compounds from safflower on some index of promoting blood circulation and regulating menstruation.

ETHNOPHARMACOLOGICAL RELEVANCE: Carthamus tinctorius is used as one of the Traditional Chinese Medicine (TCM) materials in prescriptions and … had significant effect on Fe(3+) reduction power (P<0.001 vs. negative control). Safflower extract, cytidine, 6-hydroxy-kaempferol-3,6-di-O-β-d-glucoside-7-O-β-d-glucuronide, 6-hydroxykaemp-ferol-3,6,7-tri-O-β-D-glucoside and keampferol-3-O-β-rutinoside significantly promoted ovarian granulosa cell proliferation. CONCLUSION: Based on previous researches, …

The genomic and transcriptomic landscape of metastastic urothelial cancer.

Metastatic urothelial carcinoma (mUC) is a lethal cancer, with limited therapeutic options. Large-scale studies in early settings provided critical insights into the genomic and transcriptomic characteristics of non-metastatic UC. The genomic landscape of mUC remains however unclear. Using Whole Exome (WES) and mRNA sequencing (RNA-seq) performed on metastatic biopsies from 111 patients, we show that driver genomic alterations from mUC were comparable to primary UC (TCGA data). APOBEC, platin, and HRD mutational signatures are the most prevalent in mUC, identified in 56%, 14%, and 9% of mUC sa

Characterization of anti-HIV activity mediated by R88-APOBEC3G mutant fusion proteins in CD4+ T cells, peripheral blood mononuclear cells, and macrophages.

In this study, we characterized the anti-HIV activities of various R88-APOBEC3G (R88-A3G) mutant fusion proteins in which each A3G mutant was fused with a virus-targeting polypeptide (R14-88, hereafter named R88) derived from HIV-1 Vpr. Our results show that the introduction of the deaminase-defective mutant E259Q into R88-A3G did not affect the virion incorporation of this mutant but blocked the protein's ability to inhibit HIV-1 infection. Our data also reveal that the antiviral effect of A3GY124A, a previously described A3G virus-packaging mutant, was completely rescued when the mutant was

Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia.

Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clin

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… One of the initial studies found decitabine and azacytidine, another cytidine-analog, to induced gene expression via DNA demethylation ( Figure 1 A–C) [ 16 ]. … Azacitidine (5-azacytidine), an analog of cytidine with similar structure to decitabine, acts as a DNMT inhibitor by modifying the 5th carbon of the pyrimidine ring ( Figure 1 A). …

Revealing the pharmacological effects of Remodelin against osteosarcoma based on network pharmacology, acRIP-seq and experimental validation.

Osteosarcoma (OS) is the most common primary malignant tumor of bone. Remodelin, an inhibitor of the N (4)-Acetylcytidine (ac4C) acetylation modifying enzyme N-acetyltransferase 10 (NAT10), has been shown to have therapeutic effects on cancer in several studies, and our previous studies have confirmed the inhibitory effect of Remodelin on OS cells, however, the mechanism of action has not yet been elucidated. We used network pharmacological analysis to quantify the therapeutic targets of Remodelin against OS. acRIP-seq and RNA-seq were performed to investigate the inhibitory activity of Remode…

Demethylating Agents in the Treatment of Cancer.

Gene silencing resulting from aberrant DNA methylation can lead to tumorigenesis. Therefore, drugs that inhibit or interfere with DNA methylation have been used to reactivate and induce silenced gene re-expression in malignancies. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of myelodysplastic syndromes (MDS) by the U.S. Food and Drug Administration (FDA), and are now considered the standard of care in MDS. In this review, we discuss clinical data, including clinical benefits and toxicities, which led to the approval of azacitidine and decitabine. We als

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… Mechanistics Azacitidine and its deoxy derivative decitabine are cytidine analogs that contain a nitrogen in place of the 5-carbon of the pyrimidine ring. … Likewise, decreases in dCK and increases in cytidine deaminase may confer drug resistance [ 44 , 47 , 135 , 136 ]. 6. …

Roles of LINC01473 and CD74 in osteoblasts in multiple myeloma bone disease.

The suppression of osteoblast (OB) activity is partially responsible for multiple myeloma (MM) bone disease. Long non-coding RNAs (lncRNAs) play a vital role in bone formation and resorption. However, their functions in OBs from patients with MM have rarely been reported. Through high-throughput sequencing of OBs from patients with MM and healthy controls, we identified several lncRNAs and messenger RNAs (mRNAs) with different expression profile and validated them using quantitative real-time PCR. In total, 22 upregulated and 21 downregulated lncRNAs were found in OBs from patients with MM. Mo

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… Four upregulated lncRNAs, namely, LINC01473, cytidine/uridine monophosphate kinase 2 (CMPK2), single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), and casein kinase 1 delta (CSNK1D) and two upregulated co-expression mRNAs, CD74 and histone cluster 1 H1 family member d (HIST1H1D) were … Levels of cytidine/uridine monophosphate kinase 2 (CMPK2) (B), single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) (C), and casein kinase 1 delta (CSNK1D) (D) demonstrate no significant changes. Level of CD74 mRNA in patients with MM is higher than that in healthy controls (E). …

Sialyltransferase Inhibitors for the Treatment of Cancer Metastasis: Current Challenges and Future Perspectives.

Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic acid recognition pathway and leads to deterioration of cell motility and invasion. A vast amount of evidence for the in vitro and in vivo effects of sialyltransferase inhibition or knockdown on tumor progression and tumor cell meta

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… As a proof of concept, cytidine monophosphate (CMP) inhibition of ST8Sia-II reduced tumor cell surface polysialic acid expression and tumor cell migration [ 97 ]. … The second group of ST inhibitors includes 15 – 21 , all of which has a 2-deoxy-2,3-dehydro-acetylneuraminic moiety attached to cytidine through different carboxylic acid and amide linker groups [ 128 ]. …

Some mechanisms of FLIP expression in inhibition of HIV-1 replication in Jurkat cells, CD4+ T cells and PBMCs.

HIV-1 infection and replication are affected by host factors. Recent studies demonstrate that molecules from apoptotic pathways regulate HIV-1 replication. Therefore, studies on effects of host factors that maintain host cell survival and influence HIV-1 replication are critical to understanding the mechanisms of HIV-1 replicative cycle. Using the susceptible Jurkat cell line, CD4(+) T cells, and peripheral blood mononuclear cells (PBMCs), we studied the role of FLIP, an inhibitor of caspase-8, in HIV-1 production. Full length cellular FLIP (cFLIP) inhibited HIV-1 replication in these cells. c

Sex Differences in Multiple Myeloma Biology but not Clinical Outcomes: Results from 3894 Patients in the Myeloma XI Trial.

BackgroundSex differences in the incidence and outcomes of several cancers are well established. Multiple myeloma (MM) is a malignant plasma cell dyscrasia accounting for 2% of all new cancer cases in the UK. There is a clear sex disparity in MM incidence, with 57% of cases in males and 43% in females. The mechanisms behind this are not well understood and the impact of sex on patient outcomes has not been thoroughly explored.Patients and methodsWe investigated the association of sex with baseline disease characteristics and outcome in 3894 patients recruited to the phase III UK NCRI Myeloma X

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… CSR is a multistep process that relies on the expression of activation-induced cytidine deaminase (AID) 18 . AID functions by deaminating cytidine which, coupled with base-excision repair or mismatch repair machinery, leads to the creation of mutations 19 . … Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair Adv Immunol 122 2014 1 57 24507154 10.1016/B978-0-12-800267-4.00001-8 PMC4150736 19 Kumar R DiMenna LJ Chaudhuri J Biological function of activation-induced cytidine …

The Rate of Infusion Represents an Important Aspect of Administering Anticancer Agents.

BackgroundInfusion rate is one of the essential elements that should be included in all intravenous orders. Patients may experience adverse consequences or risks associated with inappropriate infusion. Meanwhile, there is growing pressure on the chemotherapy unit to deliver treatment quickly, efficiently, and safely, and thus it is very necessary to improve the chemotherapy process and service to cancer patients. Clinicians should consider how to further standardize infusion therapy, and innovate new infusion strategies to increase efficacy, reduce toxicity, improve patient satisfaction and sa

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… Table 1 Concerns About Choice of Infusion Rate of Anticancer Agents Abbreviations : CDA, cytidine deaminase; SCL28A3, solute carrier family 28 member 3; HSRs, hypersensitivity reactions; SLCO1B1, solute carrier organic anion transporter family member 1B1. … The pharmacological advantage of prolonged dose rate gemcitabine is restricted to patients with variant alleles of cytidine deaminase c.79A>C. Asia Pac J Clin Oncol . 2011;7(1):65–74. doi: 10.1111/j.1743-7563.2010.01354.x 51. Ramsey LB, Panetta JC, Smith C, et al. …

B12 as a Treatment for Peripheral Neuropathic Pain: A Systematic Review.

Neuropathic pain describes a range of unpleasant sensations caused by a lesion or disease of the somatosensory nervous system. The sensations caused by neuropathic pain are debilitating and improved treatment regimens are sought in order to improve the quality of life of patients. One proposed treatment for neuropathic pain is vitamin B12, which is thought to alleviate pain by a number of mechanisms including promoting myelination, increasing nerve regeneration and decreasing ectopic nerve firing. In this paper, the evidence for B12 as a drug treatment for neuropathic pain is reviewed. Twenty

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… Goldberg et al., 2017 [ 32 ] | RCT | Degenerative orthopaedic alteration with neural compression | Oral cytidine monophosphate disodium uridine triphosphate trisodium and hydroxocobalamin versus oral hydroxocobalamin alone. | Both arms had a statistically significant reduction in pain measured by VAS … A double-blind, randomized, comparative study of the use of a combination of uridine triphosphate trisodium, cytidine monophosphate disodium, and hydroxocobalamin, versus isolated treatment with hydroxocobalamin, in patients presenting with compressive neuralgias. [(accessed on 19 June 2020)];J. …