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Erythropoiesis: insights into pathophysiology and treatments in 2017.

Erythropoiesis is a tightly-regulated and complex process originating in the bone marrow from a multipotent stem cell and terminating in a mature, enucleated erythrocyte.Altered red cell production can result from the direct impairment of medullary erythropoiesis, as seen in the thalassemia syndromes, inherited bone marrow failure as well as in the anemia of chronic disease. Alternatively, in disorders such as sickle cell disease (SCD) as well as enzymopathies and membrane defects, medullary erythropoiesis is not, or only minimally, directly impaired. Despite these differences in pathophysiolo

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… Hypomethylating agents DNA-methyl transferases are a family of enzymes that catalyze the transfer of methyl groups to cytidine nucleotides of genomic DNA. DNA-methyl transferase 1 (DNMT1) is a chromatin-modifying enzyme that maintains methylation marks on DNA throughout cell division. … Methylation of DNA is important for epigenetic gene regulation and has been shown to silence genes that direct the epigenetic silencing of the HbF gene, specifically BCL11A (Zhou et al. 2010 ). 5- azacitidine and 5-aza-2′-deoxycytidine (decitabine) are cytidine analogues that cause DNA hypomethylation …

Gene editing and CRISPR in the clinic: current and future perspectives.

Genome editing technologies, particularly those based on zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR (clustered regularly interspaced short palindromic repeat DNA sequences)/Cas9 are rapidly progressing into clinical trials. Most clinical use of CRISPR to date has focused on ex vivo gene editing of cells followed by their re-introduction back into the patient. The ex vivo editing approach is highly effective for many disease states, including cancers and sickle cell disease, but ideally genome editing would also be applied to diseases whic

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… An elegant solution to this problem was developed by David Liu of Harvard University, who demonstrating that fusing a cytidine deaminase (enzyme which deaminates a cytosine into a uracil) with catalytically inactive Cas9 (dCas9) could result in sgRNA-guided correction of a range of C to T mutations that … Instead, the presence of a stretch of ssDNA in the R-loop of the dCas9 serves as a substrate for the cytidine deaminase (in this case, rat APOBEC1, which showed the highest activity of the four enzymes tried). …

Mechanistic insights into bone destruction in multiple myeloma: Cellular and molecular perspectives.

Multiple myeloma (MM) is a hematological malignancy that leads to significant bone destruction, resulting in debilitating pain and skeletal-related events. The pathophysiology of osteolytic bone destruction in MM involves complex interactions between malignant plasma cells (PCs) and the bone marrow (BM) microenvironment. This review aims to provide a comprehensive synthesis of the cellular and molecular pathways underlying MM-associated bone disease. We discuss the role of osteoclast (OC), osteoblast (OB), osteocytes, along with the complex interactions between immune cells and the BM microenv

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… Interestingly, it has recently been reported that dendritic cell-mediated activation induces activation-induced cytidine deaminase (AID)-dependent genomic instability in human MM cells. This effect is mediated by RANKL, as pretreatment with anti-RANKL antibodies resulted in AID inhibition [139] . … Dendritic cell-mediated activation-induced cytidine deaminase (AID)-dependent induction of genomic instability in human myeloma. Blood. 2012;119(10):2302–2309. doi: 10.1182/blood-2011-08-376236. 140. Iyer S.P., Beck J.T., Stewart A.K., Shah J., Kelly K.R., Isaacs R., Bilic S., Sen S., Munshi N.C. …

Keyword Index for Volume 110

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… covariates 304 C-reactive protein 183 cross-talk 1199 CRPC 1634 cutaneous squamous cell carcinoma 520 CXCL12 1179 CXCL16 1535 CXCR4 686, 1179, 1288, 2261 CXCR6 1535 CXCR7 1179 cyclic adenosine mono-phosphate 1278 cyclooxygenase inhibitors 2378 cyclophosphamide 1733 cystectomy 1759 cysteine 71 cytidine …

Outcome of therapy-related myeloid neoplasms treated with azacitidine.

BackgroundTherapy-related myeloid neoplasms (t-MN), including myelodysplastic syndromes and acute myeloid leukemia (t-MDS and t-AML) are associated to clinical and biologic unfavorable prognostic features, including high levels of DNA methylation.MethodsWe retrospectively evaluated 50 t-MN patients (34 MDS and 16 AML) selected among all patients receiving azacitidine (AZA) at 10 Italian Hematology Centers. Patients had developed a t-MN at a median of 6.5 years (range 1.7- 29) after treatment of the primary tumor (hematological neoplasm, 27 patients; solid tumor, 23 patients).ResultsThe overall

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… Carcinogenicity and haemoglobin synthesis induction by cytidine analogues. Br J Cancer. 1988;857:395–402. doi: 10.1038/bjc.1988.89. …

Cancer immunity and immunotherapy beyond COVID-19.

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… Supplementary file 1 (PDF 107 kb) Supplementary file 2 (DOCX 21 kb) Abbreviations Alleanza contro il cancro Adoptive cell therapy Associazione Italiana di oncologia medica Acute myeloid leukemia Antigen presenting cell Bacille-Calmette-Guérin Carcinoma-associated fibroblast Cytidine deaminase …

Alendronate-coated long-circulating liposomes containing 99mtechnetium-ceftizoxime used to identify osteomyelitis.

Osteomyelitis is a progressive destruction of bones caused by microorganisms. Inadequate or absent treatment increases the risk of bone growth inhibition, fractures, and sepsis. Among the diagnostic techniques, functional images are the most sensitive in detecting osteomyelitis in its early stages. However, these techniques do not have adequate specificity. By contrast, radiolabeled antibiotics could improve selectivity, since they are specifically recognized by the bacteria. The incorporation of these radiopharmaceuticals in drug-delivery systems with high affinity for bones could improve the

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… Ebetino FH Rogers MJ Mechanisms of action of biphosphonates: similarities and differences and their potential influence on clinical efficacy Osteoporosis Int 2008 19 733 759 10.1007/s00198-007-0540-8 18214569 22 Schott H Goltz D Schott TC Jauch C Schwendener RC N 4 -[Alkyl-(hydroxyphosphono)phosphonate]-cytidine-new …

NAT10 Regulates LPS-Induced Inflammation via Stabilization of N4-Acetylated PTX3 mRNA in Human Dental Pulp Stem Cells.

Severe dental pulp inflammation can lead to tissue lysis and destruction, underscoring the necessity for effective treatment of pulpitis. N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification has recently emerged as a key regulator in inflammatory processes. However, whether NAT10 affects the inflammatory response in human dental pulp stem cells (hDPSCs) remains unelucidated. In this study, elevated NAT10 expression was observed in pulpitis tissues and LPS-stimulated hDPSCs. Knockdown of NAT10 led to reduced inflammatory gene expression and lower reactive oxygen species…

Восстановление ТРНС последнего универсального общего пастора (Общества) на пути к восстановлению системы перевода Древних.

Реконструирование ансестральной последовательности (АСР) было использовано для изучения эволюции переводческой системы путем определения последовательности tRNA в "Last Archaeal Common Ancestor" (LACA), "Last Bacterial Common Ancestor" (LBCA) и "Last Universal Common Ansancestor" (LUCA), которые в наших предыдущих исследованиях назывались "Общество". Составное филогенетическое дерево, взятое из реконструированных последовательности ТРНА, выявило топологию, отличную от ранее выведенных аминоачил-тРНА синтетазы (АРС). Такая непоследовательность может отражать изменения в структурных особенностях

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… Proc Natl Acad Sci USA 93:6953–6958. 10.1073/pnas.93.14.6953 Ikeuchi Y, Kimura S, Numata T, Nakamura D, Yokogawa T, Ogata T, Wada T, Suzuki T, Suzuki T (2010) Agmatine-conjugated cytidine in a tRNA anticodon is essential for AUA decoding in archaea. … Eur J Biochem 266:1128–1135. 10.1046/j.1432-1327.1999.00965.x Mandal D, Köhrer C, Su D, Russell SP, Krivos K, Castleberry CM, Blum P, Limbach PA, Söll D, RajBhandary UL (2010) Agmatidine, a modified cytidine in the anticodon of archaeal tRNA Ile , base pairs with adenosine but not with guanosine. …

The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia.

Disease relapse represents by far the most frequent cause of hematopoietic cell transplantation (HCT) failure. Patients with acute leukemia suffering relapse after HCT have limited conventional treatment options with little possibility of cure and represent, de facto, suitable candidates for the evaluation of novel cellular and biological-based therapies. Donor lymphocyte infusions (DLI) has been one of the first cellular therapies adopted to treat post HCT relapse of acute leukemia patients and still now, it is widely adopted in preemptive and prophylactic settings, with renewed interest for

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… Hypomethylating agents Hypomethylating agents Nucleoside analogs of cytidine, hypomethylating agents (HMA) are DNA methylation blockers, approved for the treatment of AML and MDS. … The Group Francophone del Myélodysplasies is conducting a prospective single-arm phase II trial evaluating the efficacy of a novel product based on the combination of oral decitabine and cedazuridine, a novel cytidine deaminase inhibitor, associated with late DLI after allogenic HCT in very high risk …

CRISPR-Cas: Converting A Bacterial Defence Mechanism into A State-of-the-Art Genetic Manipulation Tool.

Bacteriophages are pervasive viruses that infect bacteria, relying on their genetic machinery to replicate. In order to protect themselves from this kind of invader, bacteria developed an ingenious adaptive defence system, clustered regularly interspaced short palindromic repeats (CRISPR). Researchers soon realised that a specific type of CRISPR system, CRISPR-Cas9, could be modified into a simple and efficient genetic engineering technology, with several improvements over currently used systems. This discovery set in motion a revolution in genetics, with new and improved CRISPR systems being

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… Coupling this Cas9n or dCas9, the catalytically “dead” variant of Cas9, with a cytidine deaminase enzyme enables the gRNA-mediated deamination of cytosine (C) bases in the non-target DNA strand into uracil (U), which shares the base-pairing properties of thymine (T) [ 82 ]. … Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions. Nat. Biotechnol. 2017;35:371–376. doi: 10.1038/nbt.3803. 85. Rees H.A., Komor A.C., Yeh W.H., Caetano-Lopes J., Warman M., Edge A.S.B., Liu D.R. …

Sex Differences in Cancer and Cardiotoxicity: Mechanisms, Outcomes, and Clinical Implications Across Solid and Hematological Malignancies.

Sex differences influence cancer incidence, treatment response, and susceptibility to cardiovascular toxicity. Males exhibit higher rates and poorer outcomes in most non-sex-specific cancers, while females more frequently experience treatment-related adverse events, including cancer therapy-related cardiac dysfunction. Biological factors such as hormonal status, genetic polymorphisms, immune responses, and pharmacokinetics contribute to these disparities. In cardio-oncology, women-particularly premenopausal or with specific genotypes-may be at increased risk for cardiotoxicity after treatment

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… Differences in drug metabolism may also contribute to the worse outcome in men compared to women, since a higher cytidine deaminase activity in men is associated with a faster azacitidine/decitabine clearance and a suboptimal therapeutic effect [ 63 ]. … Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy Clin. Cancer Res. 2013 19 938 948 10.1158/1078-0432.CCR-12-1722 23287564 PMC3577958 64. Ansarian M.A. Fatahichegeni M. …

What nature has to offer: Opportunities for immuno-oncology.

Recent rapid development of cancer therapy has come about with the paradigm shift from the traditional goal of targeting cancer cells themselves, to reprograming the immune tumor microenvironment. Accumulating evidence shows that compounds that target epigenetic regulation, called epidrugs, play a crucial role in mediating the immunogenicity of cancer cells and in reshaping antitumor immunity. A large body of literature has recognized natural compounds as epigenetic modulators for their immunomodulatory effects and anticancer potential. Unifying our understanding of the role of these biologica

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… Nucleoside analogues that have been approved by the FDA to treat acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are 5-aza cytidine and decitabine (5-aza-2′-deoxycytidine). … Guadecitabine (SGI-110), a next-generation DNMT inhibitor, is being tested for its capacity to withstand cytidine deaminase-mediated degradation, resulting in extended action in vivo . …

Bisphosphonate conjugation for bone specific drug targeting.

Bones provide essential functions and are sites of unique biochemistry and specialized cells, but can also be sites of disease. The treatment of bone disorders and neoplasia has presented difficulties in the past, and improved delivery of drugs to bone remains an important goal for achieving effective treatments. Drug targeting strategies have improved drug localization to bone by taking advantage of the high mineral concentration unique to the bone hydroxyapatite matrix, as well as tissue-specific cell types. The bisphosphonate molecule class binds specifically to hydroxyapatite and inhibits

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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. Organomet. … N(4)-[Alkyl-(hydroxyphosphono)phosphonate]-cytidine-new drugs covalently linking antimetabolites (5-FdU, araU or AZT) with bone-targeting bisphosphonates (alendronate or pamidronate) Bioorg. Med. Chem. 19 11 2011 3520 3526 21536448 10.1016/j.bmc.2011.04.015 Schott S. …

Navigating the Landscape of Exosomal microRNAs: Charting Their Pivotal Role as Biomarkers in Hematological Malignancies.

Under physiological and pathological conditions, all cells release extracellular vesicles named exosomes, which act as transporters of lipidic, protein, and genetic material from parent to recipient cells. Neoplastic cells can secrete higher number of exosomes to exert pro-tumoral effects such as microenvironmental changes, disease progression, immunosuppression and drug-resistance. This holds true for both organ-specific cancers and hematologic malignancies. One of the most important components of exosomal cargo are microRNAs which can mediate all the abovementioned effects. More specifically

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… This observation gains further significance considering that APOBEC3A is a cytidine deaminase involved in RNA editing and innate immune responses. … Originally identified as a mediator of G>A editing in Wilms’Tumor 1 ( WT1 ) transcripts in cord blood mononuclear cells, APOBEC3A has since been shown to catalyze canonical cytidine-to-uridine (C>U) RNA editing in human monocytes and macrophages, underscoring its broader involvement in innate immune …

Advancing CRISPR genome editing into gene therapy clinical trials: progress and future prospects.

Genome editing has recently evolved from a theoretical concept to a powerful and versatile set of tools. The discovery and implementation of CRISPR-Cas9 technology have propelled the field further into a new era. This RNA-guided system allows for specific modification of target genes, offering high accuracy and efficiency. Encouraging results are being announced in clinical trials employed in conditions like sickle cell disease (SCD) and transfusion-dependent beta-thalassaemia (TDT). The path finally led the way to the recent FDA approval of the first gene therapy drug utilising the CRISPR/Cas

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… The nickase version of Cas9 (Cas9n) induces a nick on the top strand (indicated by the blue arrow), while the cytidine deaminase transforms cytosine into uracil. The comprehensive conversion of a C•G to T•A base pair is accomplished through the specified steps. … Base editors are chimeric proteins consisting of a DNA-targeting module fused to a single-stranded DNA-modifying enzyme, such as cytidine deaminase or adenine deaminase, capable of directly converting one DNA base to a specific other (Refs 24 , 25 ). …

Clonotypic characterization defines B-cell drivers of clonal expansion and intratumor heterogeneity in IgM monoclonal gammopathies.

Waldenström macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS) share the same cell of origin but differ in clonal size. Compared with other B-cell neoplasms, the lymphoplasmacytic clone in WM can be rather small, limiting our understanding of clonal expansion. We applied an integrative approach using single-cell RNA with B-cell receptor (BCR) sequencing, the assay for transposase-accessible chromatin, and whole-genome sequencing to characterize the tumor clone in patients with IgM MGUS, smoldering WM (SWM), and symptomatic WM (WM). IgM MGUS and low- or int

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… These results reflect aging‐related processes as the predominantly mutational force in IgM gammopathy, followed by the activation‐induced cytidine deaminase (AID) poly‐eta activity. Genomic landscape of the cohort . …

The Complexities of Diagnosis with Co-Existing Gaucher Disease and Hemato-Oncology-A Case Report and Review of the Literature.

Hematological abnormalities are the most common early symptoms of Gaucher disease (GD), with an increased risk of hematopoietic system malignancies reported in patients with GD. GD may be associated with monoclonal and polyclonal gammopathies; however, the mechanism of association of GD with multiple myeloma (MM) remains uncertain. Enzyme replacement therapy (ERT) has been shown to improve patients' cytopenia and it seems to facilitate anti-myeloma therapy in patients with co-occurring GD and MM. Although it is necessary to demonstrate the deficiency of enzymatic activity, as well as using gen

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… Dendritic cell-mediated activation-induced cytidine deaminase (AID)-dependent induction of genomic instability in human myeloma Blood 2012 119 2302 2309 10.1182/blood-2011-08-376236 22234692 PMC3311257 28. Dubot P. Astudillo L. Therville N. Sabourdy F. Stirnemann J. Levade T. Andrieu-Abadie N. …

Clinical outcomes of chemotherapy in cancer patients with different ethnicities.

BackgroundChoosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup.Recent findingsPharmacogenomics, the study of how an individual's g

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… PD) a | Ethnic variability of PK/PD Azacitidine | Intravenous Injection; 75 mg/m 2 | Cmax: 750 ng/mL (SC) Tmax: SC: 0.5 hr PO: 1 hr F SC: ~89% relative to IV PO: ~11% relative to SC Protein bound: ~6–12% (PO) Blood‐to‐plasma ratio: ~0.3 (PO) Vd: IV: 76 L, PO: 881 L M: hydrolysis and deamination via cytidine … deaminase CL: 167 L/h (SC) t 1/2 PO: ~0.5 h; SC or IV: 4 h E: PO: <2% unchanged (urine) IV: 85% (urine); <1% (feces) SC: 50% (urine) | Pyrimidine analog of cytidine that inhibits DNA/RNA methyltransferases Azacitidine is incorporated into RNA and DNA following cellular uptake and enzymatic biotransformation …

Immunosenescence, Physical Exercise, and their Implications in Tumor Immunity and Immunotherapy.

Aging is associated with a decline in immune function, termed immunosenescence, which compromises host defences and increases susceptibility to infections and cancer. Physical exercise is widely recognized for its myriad health benefits, including the potential to modulate the immune system. This review explores the bidirectional relationship between immunosenescence and physical exercise, focusing on their interplay in shaping antitumor immunity. We summarize the impact of aging on innate and adaptive immune cells, highlighting alterations that contribute to immunosenescence and cancer develo

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… This state is worsened by a decline in the expression of activation-induced cytidine deaminase (AID) due to the downregulation of the transcription factor E47. As a result, class switch recombination and affinity maturation are prevented 85 . … Abbreviations activation-induced cytidine deaminase acute myeloid leukemia antigen-presenting cells a proliferation-inducing ligand B-cell-activating factor B-cell receptors body mass index cyclic adenosine monophosphate chimeric antigen receptor classic DCs dendritic cells diffuse large …