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Medicinal Chemistry Research : An... 2023Mysterious evolution of a new strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the Omicron variant, led to a new challenge in the persistent...
Mysterious evolution of a new strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the Omicron variant, led to a new challenge in the persistent coronavirus disease 2019 (COVID-19) battle. Objecting the conserved SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) together using one ligand is a successful new tactic to stop SARS-CoV-2 multiplication and COVID-19 progression. The current comprehensive study investigated most nucleoside analogs (NAs) libraries, searching for the most ideal drug candidates expectedly able to act through this double tactic. Gradual computational filtration afforded six different promising NAs, riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir. Further biological assessment proved that riboprine and forodesine are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC values of about 0.21 and 0.45 μM for riboprine and about 0.23 and 0.70 μM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. These biochemical findings were supported by the prior in silico data. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading. These findings suggest that riboprine and forodesine could serve as prospective lead compounds against COVID-19. Graphical abstract.
PubMed: 36593869
DOI: 10.1007/s00044-022-02970-3 -
American Journal of Hematology Mar 2023
Common kinase mutations do not impact optimal molecular responses in core binding factor acute myeloid leukemia treated with fludarabine, cytarabine, and G-CSF based regimens.
Topics: Humans; Cytarabine; Granulocyte Colony-Stimulating Factor; Leukemia, Myeloid, Acute; Vidarabine; Mutation; Core Binding Factors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36565294
DOI: 10.1002/ajh.26811 -
International Journal of Hematology Apr 2023Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed...
Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.
Topics: Humans; Retrospective Studies; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Bone Marrow; Transcription Factors; Graft vs Host Disease; Unrelated Donors; Transplantation Conditioning; Vidarabine; MDS1 and EVI1 Complex Locus Protein
PubMed: 36515795
DOI: 10.1007/s12185-022-03505-7 -
Acta Haematologica 2023
High Incidences of Acute and Chronic Graft-Versus-Host Disease after Hematopoietic Cell Transplants for Acute Myeloid Leukemia Using Thiotepa, Busulfan, and Fludarabine Pretransplant Conditioning.
Topics: Humans; Busulfan; Thiotepa; Hematopoietic Stem Cell Transplantation; Bronchiolitis Obliterans Syndrome; Incidence; Leukemia, Myeloid, Acute; Vidarabine; Transplantation Conditioning; Graft vs Host Disease; Retrospective Studies
PubMed: 36446340
DOI: 10.1159/000528306 -
American Journal of Hematology Feb 2023
Efficacy of front-line ibrutinib versus fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: A retrospective multicenter "Real-World" study.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Cyclophosphamide; Vidarabine; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36349541
DOI: 10.1002/ajh.26779 -
Computational and Mathematical Methods... 2022Data from single-cell RNA sequencing (RNA-seq) of CLL patients were obtained from the Gene Expression Omnibus database. The R package was utilized to analyze the data,...
Analysis of Data on Fludarabine, Cyclophosphamide, and Rituximab Chemoimmunotherapy for Chronic Lymphocytic Leukemia Shows High Patient Heterogeneity and the Need for More Consideration of Individualized Treatment.
METHODS
Data from single-cell RNA sequencing (RNA-seq) of CLL patients were obtained from the Gene Expression Omnibus database. The R package was utilized to analyze the data, and the relation of results was predicted via the GeneMANIA website. The information of 7 samples covered three stages: observation stage, pretreatment by CIT with rituximab, fludarabine, and cyclophosphamide (pre-CIT), and post-CIT. The differentially expressed genes (DEGs) were identified, and functional enrichment analyses were performed. B cell subpopulations and pseudotime trajectories analysis was conducted.
RESULTS
A total of 70,659 DEGs were identified. Each patient's DEGs presented their own characteristics, with low similarity. Therefore, it is difficult to identify potential hub genes. Similarly, pathway enrichment analysis showed significant tumor heterogeneity among CLL patients. Analysis of relapsed post-CIT compared to the observation stage suggested that the pathway should be taken seriously as it is closely related to treatment strategy and patient prognosis.
CONCLUSIONS
Tumor heterogeneity may be a more common manifestation of CLL. Individualized treatment should be considered for CLL. abnormality and its regulatory factors should still be the focus of CLL diagnosis and treatment.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Vidarabine
PubMed: 36226246
DOI: 10.1155/2022/7451395 -
ChemMedChem Dec 2022Repurposing of antiviral drugs affords a rapid and effective strategy to develop therapies to counter pandemics such as COVID-19. SARS-CoV-2 replication is closely...
Effects of the 5'-Triphosphate Metabolites of Ribavirin, Sofosbuvir, Vidarabine, and Molnupiravir on CTP Synthase Catalysis and Filament Formation: Implications for Repurposing Antiviral Agents against SARS-CoV-2.
Repurposing of antiviral drugs affords a rapid and effective strategy to develop therapies to counter pandemics such as COVID-19. SARS-CoV-2 replication is closely linked to the metabolism of cytosine-containing nucleotides, especially cytidine-5'-triphosphate (CTP), such that the integrity of the viral genome is highly sensitive to intracellular CTP levels. CTP synthase (CTPS) catalyzes the rate-limiting step for the de novo biosynthesis of CTP. Hence, it is of interest to know the effects of the 5'-triphosphate (TP) metabolites of repurposed antiviral agents on CTPS activity. Using E. coli CTPS as a model enzyme, we show that ribavirin-5'-TP is a weak allosteric activator of CTPS, while sofosbuvir-5'-TP and adenine-arabinofuranoside-5'-TP are both substrates. β-d-N -Hydroxycytidine-5'-TP is a weak competitive inhibitor relative to CTP, but induces filament formation by CTPS. Alternatively, sofosbuvir-5'-TP prevented CTP-induced filament formation. These results reveal the underlying potential for repurposed antivirals to affect the activity of a critical pyrimidine nucleotide biosynthetic enzyme.
Topics: Humans; Ribavirin; Sofosbuvir; Antiviral Agents; SARS-CoV-2; Vidarabine; Escherichia coli; COVID-19; Cytidine
PubMed: 36184568
DOI: 10.1002/cmdc.202200399 -
Bone Marrow Transplantation Dec 2022
Topics: Humans; Pentostatin; Vidarabine; Cyclophosphamide; Transplantation Conditioning; Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation
PubMed: 36115868
DOI: 10.1038/s41409-022-01819-y -
American Journal of Hematology Dec 2022We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic...
We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic cell transplantation (HCT) in contemporary real-world patients. We evaluated the cumulative incidence of AdV disease, as well as risk factors, survival, and treatment details, among 25 233 patients who underwent autologous HCT and 48 380 patients who underwent allogeneic HCT between 2005 and 2019. The 1-year cumulative incidences of AdV disease after autologous and allogeneic HCT were 0.18% and 1.52%, respectively, in children, and 0.49% and 2.99%, respectively, in adults. Among patients with AdV disease, renourinary infection was the most common manifestation, and viremia or disseminated disease occurred in 6% of those after autologous HCT and 19% of those after allogeneic HCT. In multivariate analysis, age ≥50 years and lymphoma were associated with AdV disease after autologous HCT, while patients age ≥50 years, male patients, lymphoma, HCT-specific comorbidity index ≥3, human leukocyte antigen-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, HCT from 2005 to 2009, acute graft-versus-host disease (GVHD), and chronic GVHD were associated with AdV disease after allogeneic HCT. The 1-year probabilities of survival after disease diagnosis were 65% in autologous HCT and 44% in allogeneic HCT. Regardless of the AdV disease burden, there was an increased risk of mortality after both autologous and allogeneic HCT. The most commonly used antiviral agents were cidofovir and vidarabine. The probabilities of improvement and survival with currently available agents were suboptimal. AdV disease after HCT remains a challenge. Better antiviral modalities are necessary.
Topics: Adult; Child; Humans; Male; Middle Aged; Graft vs Host Disease; Japan; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning; Lymphoma; Registries; Adenoviridae
PubMed: 36087061
DOI: 10.1002/ajh.26723 -
American Journal of Hematology Nov 2022Fludarabine, cytarabine, GCSF (FLAG)-based induction/consolidation results in high remission rates in core binding factor (CBF) acute myelogenous leukemia. We treated... (Clinical Trial)
Clinical Trial
Retrospective comparison of survival and responses to Fludarabine, Cytarabine, GCSF (FLAG) in combination with gemtuzumab ozogamicin (GO) or Idarubicin (IDA) in patients with newly diagnosed core binding factor (CBF) acute myelogenous leukemia: MD Anderson experience in 174 patients.
Fludarabine, cytarabine, GCSF (FLAG)-based induction/consolidation results in high remission rates in core binding factor (CBF) acute myelogenous leukemia. We treated 174 consecutive patients with newly diagnosed CBF-AML in a prospective clinical trial of FLAG-based induction/consolidation in combination with gemtuzumab ozogamicin (FLAG-GO; N = 65) or in combination with idarubicin (FLAG-IDA; N = 109). The 5 year RFS in the FLAG-GO cohort was significantly better than the FLAG-IDA cohort, 78% versus 59%, respectively (p-value = .02). In multivariate analysis for RFS, age (p = .0001), FLAG-GO regimen (p = .04), 4 log reduction in CBF-related fusion transcript by quantitative polymerase chain reaction (qPCR) in bone marrow samples at end of consolidation therapy (p = .03), and additional cytogenetic abnormalities (p = .03) were significant variables. Lower age (p = .0001) and 3 log or more transcript reduction at end of induction (p = .04) were significant variables predicting for better overall survival (OS), while there was strong trend for better OS with FLAG-GO (p = .06) regimen. FLAG-GO regimen was superior in optimal disease specific fusion transcript reduction at end of induction (p = .002), mid-consolidation (p < .01), and end of consolidation (p < .001) therapy. Induction/consolidation with FLAG-GO regimen results in better clinical outcomes in newly diagnosed patients with CBF-AML compared to FLAG-IDA and achieves deeper molecular clearance by qPCR assessment of the fusion transcripts.
Topics: Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Core Binding Factors; Cytarabine; Gemtuzumab; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Leukemia, Myeloid, Acute; Prospective Studies; Retrospective Studies; Vidarabine
PubMed: 36053747
DOI: 10.1002/ajh.26700