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Molecules (Basel, Switzerland) May 2024DNA is constantly damaged by various external and internal factors. In particular, oxidative damage occurs in a steady state, and 8-oxo-2'-deoxyguanosine (oxodG) is...
DNA is constantly damaged by various external and internal factors. In particular, oxidative damage occurs in a steady state, and 8-oxo-2'-deoxyguanosine (oxodG) is known as the main oxidative damage. OxodG is a strong genotoxic nucleoside and is thought to be involved in the pathogenesis of cancer and neurological diseases. However, a breakthrough method to detect the position of oxodG in DNA has not yet been developed. Therefore, we attempted to develop a novel method to detect oxodG in DNA using artificial nucleosides. Recently, we have succeeded in the recognition of oxodG in DNA by a single nucleotide elongation reaction using nucleoside derivatives based on a purine skeleton with a 1,3-diazaphenoxazine unit. In this study, we developed a new nucleoside derivative with a pyrimidine skeleton in order to further improve the recognition ability and enzymatic reaction efficiency. We, therefore, designed and synthesized 2'-deoxycytidine-1,3-diazaphenoxazine (Cdap) and its triphosphate derivatives. The results showed that it was incorporated into the primer strand relative to the dG template because of its cytidine skeleton, but it was more effective at the complementary position of the oxodG template. These results indicate that the new nucleoside derivative can be considered as one of the new candidates for the detection of oxodG in DNA.
Topics: 8-Hydroxy-2'-Deoxyguanosine; DNA; Deoxycytidine; Oxazines; Deoxyguanosine; DNA Damage; Nucleotides; Polyphosphates
PubMed: 38792131
DOI: 10.3390/molecules29102270 -
International Journal of Molecular... May 2024Previous studies have documented that FOLFOX and XELOX therapies negatively impact the metabolism of skeletal muscle and extra-muscle districts. This pilot study tested...
Previous studies have documented that FOLFOX and XELOX therapies negatively impact the metabolism of skeletal muscle and extra-muscle districts. This pilot study tested whether three-month FOLFOX or XELOX therapy produced changes in plasma amino acid levels (PAAL) (an estimation of whole-body amino acid metabolism) and in plasma levels of malondialdehyde (MDA), a marker of lipid hyper oxidation. Fourteen ambulatory, resected patients with colorectal cancer scheduled to receive FOLFOX (n = 9) or XELOX (n = 5) therapy, after overnight fasting, underwent peripheral venous blood sampling, to determine PAAL and MDA before, during, and at the end of three-month therapy. Fifteen healthy matched subjects (controls) only underwent measures of PAAL at baseline. The results showed changes in 87.5% of plasma essential amino acids (EAAs) and 38.4% of non-EAAs in patients treated with FOLFOX or XELOX. These changes in EAAs occurred in two opposite directions: EAAs decreased with FOLFOX and increased or did not decrease with XELOX (interactions: from = 0.034 to = 0.003). Baseline plasma MDA levels in both FOLFOX and XELOX patients were above the normal range of values, and increased, albeit not significantly, during therapy. In conclusion, three-month FOLFOX or XELOX therapy affected plasma EAAs differently but not the baseline MDA levels, which were already high.
Topics: Humans; Colorectal Neoplasms; Male; Female; Middle Aged; Amino Acids; Antineoplastic Combined Chemotherapy Protocols; Aged; Fluorouracil; Oxaloacetates; Leucovorin; Capecitabine; Malondialdehyde; Deoxycytidine; Organoplatinum Compounds; Pilot Projects; Oxidation-Reduction; Adult; Lipid Peroxidation; Lipid Metabolism
PubMed: 38791339
DOI: 10.3390/ijms25105300 -
International Journal of Molecular... May 2024Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the... (Review)
Review
Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, mutations, and unmutated status of the immunoglobulin heavy-chain variable region () gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in or phospholipase Cγ2 (). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Leukemia, Lymphocytic, Chronic, B-Cell; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Pyrimidines; Pyrazoles; Piperidines; Adenine; Phospholipase C gamma; Antineoplastic Agents; Mutation
PubMed: 38791284
DOI: 10.3390/ijms25105246 -
Genes Apr 2024Cell-free DNA (cfDNA) has recently emerged as a promising minimally invasive diagnostic biomarker for various cancers. In this study, our aim was to identify cfDNA...
Cell-free DNA (cfDNA) has recently emerged as a promising minimally invasive diagnostic biomarker for various cancers. In this study, our aim was to identify cfDNA biomarkers by investigating genes that displayed significant differences between glioma patients and their corresponding controls. To accomplish this, we utilized publicly available data from the Gene Expression Omnibus, focusing on 5-hydroxymethylcytosine (5hmC) profiles in both cfDNA and genomic DNA (gDNA) from glioma patients and healthy individuals. The intersection of gene lists derived from these comparative analyses unveiled and as the two genes with elevated 5hmC levels in both the cfDNA of glioma patients and gDNA of glioma tissue compared to their respective controls. The gene expression data revealed both genes were upregulated in glioma tissue compared to normal brain tissue. Integration of 5hmC data revealed a strong positive correlation in the glioma tissue group between 5hmC and the gene expression of the gene. Furthermore, exploration using the AmiCa web tool indicated that gene expression was elevated compared to 17 other cancers included in the database, emphasizing its potential as a distinctive biomarker across multiple cancer types.
Topics: Humans; 5-Methylcytosine; Glioma; Cell-Free Nucleic Acids; Biomarkers, Tumor; Brain Neoplasms; Membrane Glycoproteins; Gene Expression Regulation, Neoplastic; DNA Methylation
PubMed: 38790164
DOI: 10.3390/genes15050535 -
Nature Communications May 2024Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination...
Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (
Topics: Humans; Urinary Bladder Neoplasms; Neoadjuvant Therapy; Deoxycytidine; Gemcitabine; Immunotherapy; Male; Cisplatin; Female; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Immune Checkpoint Inhibitors; Aged; Middle Aged; Neoplasm Invasiveness; Interleukin-9; B7-H1 Antigen; Biomarkers, Tumor; Treatment Outcome
PubMed: 38789460
DOI: 10.1038/s41467-024-48480-1 -
Tislelizumab combined with GT chemotherapy for intimal sarcoma of inferior vena cava: A case report.Medicine May 2024Intimal sarcoma of inferior vena cava (IVC) is a rare soft tissue sarcoma with no typical symptoms and specific imaging features in the early stage, and there is a lack...
RATIONALE
Intimal sarcoma of inferior vena cava (IVC) is a rare soft tissue sarcoma with no typical symptoms and specific imaging features in the early stage, and there is a lack of standardized treatment and methods.
PATIENT CONCERNS
A 54-year-old female patient presented to Fenghua District People's Hospital with a post-active cough and hemoptysis and was subsequently referred to our hospital.
DIAGNOSES
The patient was pathologically diagnosed as intimal sarcoma of IVC complicating multiple intrapulmonary metastases. Chest CT revealed left lung malignant tumor with multiple intrapulmonary metastases; while enhanced upper abdominal CT showed cancer embolus of IVC with extension to right atrium and bilateral renal veins. Besides, hematoxylin and eosin staining suggested intimal sarcoma of veins. Immunohistochemical staining showed positivity for PD-L1, Ki-67, CD31, Desmin and ERG.
INTERVENTIONS
The patient initially received GT chemotherapy (gemcitabine injection + docetaxel). Then, immunotherapy (tislelizumab) was added based on the results of genetic testing (TP53 gene mutation).
OUTCOMES
The disease was stabilized after receiving the treatment.
LESSONS
Given the lack of characteristic clinical manifestations in patients with intimal sarcoma of IVC, imaging examination combined with immunohistochemical index were helpful for diagnosis of intimal sarcoma of IVC. Furthermore, the combination of tislelizumab and GT chemotherapy was feasible in such patients with positive PD-L1 expression and TP53 mutation.
Topics: Humans; Female; Middle Aged; Vena Cava, Inferior; Sarcoma; Antibodies, Monoclonal, Humanized; Vascular Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Gemcitabine; Deoxycytidine; Lung Neoplasms
PubMed: 38788046
DOI: 10.1097/MD.0000000000038056 -
Cells May 2024HIV infection is an ongoing global health issue, despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed...
HIV infection is an ongoing global health issue, despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter the immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify the effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F), and tenofovir alafenamide (TAF) on the expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In the absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.
Topics: Animals; Mice; HIV Infections; Emtricitabine; Anti-Retroviral Agents; Disease Models, Animal; Male; Tenofovir; Cytokines; Heterocyclic Compounds, 3-Ring; Mice, Inbred C57BL; Immunity; Alanine; Piperazines; Amides; Pyridones
PubMed: 38786105
DOI: 10.3390/cells13100882 -
Scientific Reports May 2024The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of... (Comparative Study)
Comparative Study
The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV-MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF-RIBA, Sofosbuvir + Daclatasvir; SOF-DACLA). Regarding clinical response HCV-MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF-DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF-DACLA group (decreased at 24 weeks). In SOF-RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV-MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.
Topics: Humans; Cryoglobulinemia; Antiviral Agents; Male; Vasculitis; Middle Aged; Female; Aged; Hepacivirus; Ribavirin; Sofosbuvir; Imidazoles; Valine; Pyrrolidines; B-Cell Activating Factor; Interferon-alpha; Drug Therapy, Combination; Hepatitis C; Treatment Outcome; Hepatitis C, Chronic; Carbamates
PubMed: 38782988
DOI: 10.1038/s41598-024-60490-z -
Redox Biology Jul 2024Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in...
Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling sequencing, RNA-sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of phosphatase and tensin homolog (PTEN), consequently leading to glutathione peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic cancer. Notably, both inhibition of ARID3A and enhancement of ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic cancer.
Topics: Ferroptosis; Humans; PTEN Phosphohydrolase; Drug Resistance, Neoplasm; Pancreatic Neoplasms; Mice; DNA-Binding Proteins; Transcription Factors; Animals; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gemcitabine; Carcinoma, Pancreatic Ductal; Deoxycytidine; Cell Proliferation; Xenograft Model Antitumor Assays; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 38781729
DOI: 10.1016/j.redox.2024.103200 -
BMC Cancer May 2024International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1... (Comparative Study)
Comparative Study
BACKGROUND
International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib's cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV.
METHODS
A 3-state partitioned survival model was employed to assess ivosidenib's cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib's cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios.
RESULTS
Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib's cost and utility values on estimate uncertainty.
CONCLUSIONS
At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50-60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.
Topics: Humans; Isocitrate Dehydrogenase; Cholangiocarcinoma; Cost-Benefit Analysis; Pyridines; Taiwan; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Mutation; Glycine; Bile Duct Neoplasms; Leucovorin; Male; Female; Organoplatinum Compounds; Middle Aged
PubMed: 38778261
DOI: 10.1186/s12885-024-12362-y