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Transplant Infectious Disease : An... Nov 2023Adenovirus (AdV) infection occurs in 0-20% of patients in the first 3-4 months after allogeneic hematopoietic cell transplantation (HCT), being higher in pediatric than... (Review)
Review
Adenovirus (AdV) infection occurs in 0-20% of patients in the first 3-4 months after allogeneic hematopoietic cell transplantation (HCT), being higher in pediatric than in adult patients. About 50% of AdV infections involve the blood, which in turn, correlates with an increased risk developing AdV diseases, end-organ damage, and 6-month overall mortality. The main risk factors for AdV infection are T-cell depletion of the graft by ex vivo selection procedures or in vivo use of alemtuzumab or antithymocyte serum, development of graft versus host disease (GVHD) grade III-IV, donor type (haploidentical or human leucocyte antigen mismatched related donor > cord blood> unrelated matched donor) and severe lymphopenia (<0.2 × 10 /L). The prevention of AdV disease relies on early diagnosis of increasing viral replication in blood or stool and the pre-emptive start of cidofovir as viral load exceeds the threshold of ≥10 copies/mL in blood and/or 10 copies/g stool in the stool. Cidofovir (CDV), a cytosine monophosphate nucleotide analog, is currently the only antiviral recommended for AdV infection despite limited efficacy and moderate risk of nephrotoxicity. Brincidofovir, a lipid derivative of CDV with more favorable pharmacokinetics properties and superior efficacy, is not available and currently is being investigated for other viral infections. The enhancement of virus-specific T-cell immunity in the first few months post-HCT by the administration of donor-derived or third-party-donor-derived virus-specific T-cells represents an innovative and promising modality of intervention and data of efficacy and safety of the ongoing prospective randomized studies are eagerly awaited.
Topics: Adult; Humans; Child; Cidofovir; Prospective Studies; Adenoviridae Infections; Risk Factors; Immunologic Factors; Hematopoietic Stem Cell Transplantation
PubMed: 37846850
DOI: 10.1111/tid.14173 -
Advanced Science (Weinheim,... Sep 2023Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of...
Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl-XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib-induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl-XL. The intervention effect is dependent on the alleviation of the nilotinib-induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin-proteasome degradation of Bcl-XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl-XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.
Topics: Animals; Chloroquine; Endothelial Cells; Apoptosis; Pyrimidines; Ubiquitin-Specific Proteases
PubMed: 37452432
DOI: 10.1002/advs.202302002 -
Clinical Therapeutics Apr 2024Hypertrophic cardiomyopathy (HCM) is an under-recognized genetic cardiac disorder affecting the muscles and contractility of the heart, which in turn can result in heart... (Review)
Review
PURPOSE
Hypertrophic cardiomyopathy (HCM) is an under-recognized genetic cardiac disorder affecting the muscles and contractility of the heart, which in turn can result in heart failure symptoms, arrhythmia, and sudden cardiac death. Previously, pharmacotherapy options for HCM were not disease-specific, often poorly tolerated, and overall inadequate for optimal management. This narrative review discusses the pharmacology of the novel drug mavacamten, the clinical trials supporting its use, and considerations for its use in clinical practice.
METHODS
PubMed and ClinicalTrials.gov were searched for the key words mavacamten and Camzyos to identify currently active clinical trials and clinical trials published between January 2015 and March 2023. Data from EXPLORER-HCM were included, as EXPLORER-HCM led to approval by the US Food and Drug Administration of the use of mavacamten, along with data from VALOR-HCM, which provided additional evidence for use. Publications that were not randomized, controlled trials were not included in this review.
FINDINGS
The findings from this review suggest that mavacamten is an effective treatment for patients with persistently symptomatic obstructive HCM and may decrease the need for septal reduction therapy. Mavacamten use was associated with improved exercise capacity, left ventricular outflow tract obstruction, and New York Heart Association functional class, and with a decreased frequency of septal reduction therapy.
IMPLICATIONS
HCM is associated with significant morbidity and mortality, independent of other disease states. Mavacamten is a novel treatment option for patients with HCM and offers an additional option for patients with persistent symptoms who previously had limited treatment options. The use of mavacamten in patients with obstructive HCM may improve exercise capacity, and decrease symptoms and the need for septal reduction therapy. There is potential for mavacamten to be indicated for use in patients with nonobstructive HCM in the future, pending findings from Phase III trials in this population.
Topics: Humans; Cardiomyopathy, Hypertrophic; Treatment Outcome; Clinical Trials as Topic; Benzylamines; Uracil
PubMed: 38508915
DOI: 10.1016/j.clinthera.2024.02.007 -
Molecular Diversity Oct 2023Cyclonucleosides are a group of nucleoside derivatives which, in addition to the classical N-glycosidic bond, have an additional covalent bond (linker, bridge) in their... (Review)
Review
Cyclonucleosides are a group of nucleoside derivatives which, in addition to the classical N-glycosidic bond, have an additional covalent bond (linker, bridge) in their structure, which connects the heterocyclic base and sugar ring. The majority of them have been discovered in the laboratory; however, few such compounds have also been found in natural sources, including metabolites of sponges or radical damage occurring in nucleic acids. Due to their structural properties-rigid, fixed conformation-they have found wide applications in medicinal chemistry and biochemistry as biocides as well as enzyme inhibitors and molecular probes. They have also found use as convenient synthetic tools for the preparation of new nucleoside analogues, enabling structural modifications of both the sugar ring and heterocyclic base. This review summarizes the recent progress in the synthesis of various purine and pyrimidine cyclonucleosides using diverse chemical approaches based on radical, "click", metal-mediated, and other types of reactions. It also presents recent reports concerning possible applications in medicinal chemistry, as well as their applications as valuable key intermediates in the synthesis of sugar- and base-modified nucleoside analogues and heterocyclic compounds.
PubMed: 37889351
DOI: 10.1007/s11030-023-10740-5 -
Current Cardiology Reviews 2024Heart failure is a clinical condition with high mortality and morbidity that occurs when the heart is unable to pump enough blood to meet the metabolic demands of the... (Review)
Review
BACKGROUND
Heart failure is a clinical condition with high mortality and morbidity that occurs when the heart is unable to pump enough blood to meet the metabolic demands of the body. The pharmacological management of heart failure has been revolutionized over the past decade with novel treatments.
OBJECTIVE
The aim of the review is to highlight the recent pharmacological advances in the management of heart failure.
RESULTS
Sodium-glucose cotransporter-2 inhibitor (SGLT2i), iron carboxymaltose, finerenone, omecamtiv mecarbil, and vericiguat have been shown to reduce hospitalization for heart failure. However, only SGLT2i, vericiguat, and omecamtiv mecarbil have been shown to reduce cardiovascular death. Finerenone has been shown to reduce cardiovascular events and renal adverse outcomes in patients with diabetes and kidney disease. Currently, only SGLT2i has been studied in patients beyond the heart failure with reduced ejection fraction population.
CONCLUSION
The current quadruple therapy in the treatment of heart failure has demonstrated a reduction in the hospitalization of patients and a decrease in mortality associated with the condition. Individualized heart failure therapy research have shown some benefit in select heart failure patients. Further research on novel therapies will help improve heart failure patient outcomes.
Topics: Humans; Glucosides; Heart Failure; Heterocyclic Compounds, 2-Ring; Naphthyridines; Pyrimidines; Sodium-Glucose Transporter 2 Inhibitors; Spironolactone; Urea
PubMed: 38284706
DOI: 10.2174/011573403X270178231228061314 -
The Journal of Gene Medicine Sep 2023Monkeypox infection outbreaks have been observed sporadically in Africa, usually as a result of interaction with wildlife reservoirs. The genomes of the new strain range... (Review)
Review
Monkeypox infection outbreaks have been observed sporadically in Africa, usually as a result of interaction with wildlife reservoirs. The genomes of the new strain range in size from 184.7 to 198.0 kb and are identified with 143-214 open reading frames. Viral cores are rapidly carried on microtubules away from the cell's perimeter and deeper into the cytoplasm once the virus and cell membranes fuse. Depending on the kind of exposure, patients with monkeypox may experience a febrile prodrome 5-13 days after exposure, which frequently includes lymphadenopathy, malaise, headaches, and muscle aches. A different diagnostic approach is available for monkeypox, including histopathological analysis, electron microscopy, immunoassays, polymerase chain reaction, genome sequencing, microarrays, loop-mediated isothermal amplification technology and CRISPR (i.e., "clustered regularly interspaced short palindromic repeats"). There are currently no particular, clinically effective treatments available for the monkeypox virus. An initial treatment is cidofovir. As a monophosphate nucleotide analog, cidofovir is transformed into an inhibitor of viral DNA polymerase by cellular kinases, which is analogous to cidofovir's function in inhibiting viral DNA synthesis. The European Medicine Agency and the Food and Drug Administration have both granted permission for IMVAMUNE, a replication-deficient, attenuated third-generation modified vaccinia Ankara vaccine, to be used for the prevention of smallpox and monkeypox in adults.
Topics: United States; Humans; Mpox (monkeypox); Cidofovir; Vaccinia virus; Monkeypox virus; Clinical Laboratory Techniques
PubMed: 37132057
DOI: 10.1002/jgm.3521 -
Advances in Experimental Medicine and... 2024The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were... (Review)
Review
The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were reported in Somalia 1977 and as a laboratory infection in the UK 1978; in 1980, the World Health Organization (WHO) declared smallpox for extinct. The smallpox virus with its very high transmissibility and mortality is still a major biothreat, because the vaccination against smallpox was stopped globally in the 1980s. For this reason, new antivirals (cidofovir, brincidofovir, and tecovirimat) and new vaccines (ACAM2000, LC16m8 and Modified Vaccine Ankara MVA) were developed. For passive immunization, vaccinia immune globulin intravenous (VIGIV) is available. Due to the relationships between orthopox viruses such as vaccinia, variola, mpox (monkeypox), cowpox, and horsepox, the vaccines (LC16m8 and MVA) and antivirals (brincidofovir and tecovirimat) could also be used in the mpox outbreak with positive preliminary data. As mutations can result in drug resistance against cidofovir or tecovirimat, there is need for further research. Further antivirals (NIOCH-14 and ST-357) and vaccines (VACΔ6 and TNX-801) are being developed in Russia and the USA. In conclusion, further research for treatment and prevention of orthopox infections is needed and is already in progress. After a brief introduction, this chapter presents the smallpox and mpox disease and thereafter full overviews on antiviral treatment and vaccination including the passive immunization with vaccinia immunoglobulins.
Topics: Smallpox; Humans; Antiviral Agents; Smallpox Vaccine; Mpox (monkeypox); Vaccination; Variola virus; Animals; Cytosine; Monkeypox virus; Immunization, Passive; Organophosphonates; Isoindoles; Cidofovir; Immunoglobulins, Intravenous; Benzamides; Phthalimides
PubMed: 38801586
DOI: 10.1007/978-3-031-57165-7_19 -
Life Science Alliance Sep 2023The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo CTP production relies on CTP synthetases 1 and 2 (CTPS1 and...
The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo CTP production relies on CTP synthetases 1 and 2 (CTPS1 and CTPS2) that catalyze the conversion of UTP into CTP. CTP synthetase activity is high in proliferating cells including cancer cells; however, the respective roles of CTPS1 and CTPS2 in cell proliferation are not known. By inactivation of and/or and complementation experiments, we showed that both CTPS1 and CTPS2 are differentially required for cell proliferation. CTPS1 was more efficient in promoting proliferation than CTPS2, in association with a higher intrinsic enzymatic activity that was more resistant to inhibition by 3-deaza-uridine, an UTP analog. The contribution of CTPS2 to cell proliferation was modest when CTPS1 was expressed but essential in absence of CTPS1. Public databases analysis of more than 1,000 inactivated cancer cell lines for CTPS1 or CTPS2 confirmed that cell growth is highly dependent of CTPS1 but less or not of CTPS2. Therefore, our results demonstrate that CTPS1 is the main contributor to cell proliferation.
Topics: Carbon-Nitrogen Ligases; Uridine Triphosphate; Cell Proliferation; Cell Cycle; Cell Line
PubMed: 37348953
DOI: 10.26508/lsa.202302066 -
Oncology Reports Oct 2023Although 5‑fluorouracil (5‑FU)‑based chemotherapy is the major treatment for colorectal cancer, it has disadvantages such as systemic toxicity, lack of... (Review)
Review
Although 5‑fluorouracil (5‑FU)‑based chemotherapy is the major treatment for colorectal cancer, it has disadvantages such as systemic toxicity, lack of effectiveness and selectivity, and development of resistance. Capecitabine, a prodrug form of 5‑FU, was designed to overcome these drawbacks, to fulfill the need for more convenient therapy, and to improve safety, tolerability and intratumor drug concentration levels through a tumor‑specific conversion to the active 5‑FU drug. The purpose of the present review is to provide a comprehensive comparison between 5‑FU therapy and capecitabine. In the current review, anticancer drug classification was discussed and the development of capecitabine from the original fluorinated analogue (5‑FU) to overcome its drawbacks was explained. Specifically, 5‑FU is compared with capecitabine therapy regarding various properties, including drug metabolism, cellular mechanism, effect on the apoptosis pathway and cell cycle phases, safety and tolerability. Moreover, three metabolizing enzymes required for the activation of capecitabine to 5‑FU were discussed. Capecitabine, as monotherapy or in combination with other chemotherapies, exhibited improved drug efficacy and survival. However, the changes that mediate the chemoresistance of capecitabine treatment were classified as intracellular, extracellular or cell surface factors, or cell‑phenotype state. Future studies should examine the efficacy of capecitabine combined with novel and safe drugs other than chemotherapeutic agents that play a role in the inhibition of tumor initiation, progression and metastasis.
Topics: Humans; Capecitabine; Fluorouracil; Cell Division; Cell Membrane; Colorectal Neoplasms
PubMed: 37594133
DOI: 10.3892/or.2023.8612 -
Chemical Society Reviews Mar 2024Epigenetic phenomena play a central role in cell regulatory processes and are important factors for understanding complex human disease. One of the best understood... (Review)
Review
Epigenetic phenomena play a central role in cell regulatory processes and are important factors for understanding complex human disease. One of the best understood epigenetic mechanisms is DNA methylation. In the mammalian genome, cytosines (C) in CpG dinucleotides were long known to undergo methylation at the 5-position of the pyrimidine ring (mC). Later it was found that mC can be oxidized to 5-hydroxymethylcytosine (hmC) or even further to 5-formylcytosine (fC) and to 5-carboxylcytosine (caC) by the action of 2-oxoglutarate-dependent dioxygenases of the TET family. These findings unveiled a long elusive mechanism of active DNA demethylation and bolstered a wave of studies in the area of epigenetic regulation in mammals. This review is dedicated to critical assessment of recent data on biochemical and chemical aspects of the formation and conversion of hmC in DNA, analytical techniques used for detection and mapping of this nucleobase in mammalian genomes as well as epigenetic roles of hmC in DNA replication, transcription, cell differentiation and human disease.
Topics: Animals; Humans; Epigenesis, Genetic; 5-Methylcytosine; Cytosine; DNA; Mammals
PubMed: 38205583
DOI: 10.1039/d3cs00858d