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The Journal of Dermatological Treatment Dec 2024Brivudine has been used in herpes zoster (HZ) treatment for years, but the safety and efficacy of brivudine are inconclusive. Here we perform a meta-analysis to assess... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
Brivudine has been used in herpes zoster (HZ) treatment for years, but the safety and efficacy of brivudine are inconclusive. Here we perform a meta-analysis to assess the efficacy, safety, incidence of postherpetic neuralgia of brivudine.
METHODS
Data of randomized controlled Trials (RCTS) were obtained from the databases of both English (PubMed, Embase, and Cochrane Library) and Chinese (China National Knowledge Infrastructure, China Science Journal Database, and WanFang Database) literatures from inception to 12 September 2022. Meta-analyses of efficacy and safety of Brivudine for the treatment of herpes zoster for RCTS were conducted.
RESULTS
The analyses included seven RCTS (2095 patients in experimental group and 2076 patients in control group) in the treatment of HZ with brivudine. It suggested that the brivudine group was superior to the control group in terms of efficacy ( = .0002) and incidence of postherpetic neuralgia ( = .04). But the incidence of adverse reactions has no significant difference between the brivudine and the control groups ( = .22). In addition, subgroup analysis of adverse events also showed that brivudine was about the same safety as other modalities in the treatment of HZ ( > .05).
CONCLUSIONS
Brivudine is effective for HZ. However, the evidence on the safety of brivudine is insufficient.
Topics: Humans; Herpes Zoster; Neuralgia, Postherpetic; Antiviral Agents; Randomized Controlled Trials as Topic; Treatment Outcome; Incidence; Bromodeoxyuridine
PubMed: 38811010
DOI: 10.1080/09546634.2024.2355256 -
PloS One 2024Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic... (Randomized Controlled Trial)
Randomized Controlled Trial
Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer's disease (BenfoTeam).
BACKGROUND
Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches.
OBJECTIVE
To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD.
METHODS
This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA.
CONCLUSION
The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.
Topics: Humans; Alzheimer Disease; Thiamine; Double-Blind Method; Male; Female; Aged; Middle Aged; Treatment Outcome; Prodrugs
PubMed: 38809849
DOI: 10.1371/journal.pone.0302998 -
International Immunopharmacology Jun 2024Colorectal cancer (CRC) is a significant global health challenge, with increasing rates of incidence and mortality. Despite advancements in immunotherapy, resistance,...
Colorectal cancer (CRC) is a significant global health challenge, with increasing rates of incidence and mortality. Despite advancements in immunotherapy, resistance, particularly due to T cell exhaustion, remains a major hurdle. This study explores the role of YWHAH, mediated by N4-acetylcytidine (ac4C) modification, in CRC progression and its impact on CD8 T cell exhaustion. Analysis of five paired CRC patient tissue samples using acetylated RNA immunoprecipitation and sequencing (acRIP-seq)identified ac4C-modified mRNAs. Functional assays, including cell culture, transfection, qRT-PCR, and immune assays, investigated the influence of YWHAH expression on CRC advancement. Bioinformatics analysis of TCGA data assessed the correlation between YWHAH and immune responses, as well as checkpoint inhibitors. Flow cytometry and Immunohistochemistry validated these findings, complemented by a co-culture experiment involving CD8 T cells and CRC cell lines (LOVO and HCT116). acRIP-seq revealed YWHAH as a potential driver of CRC progression, exhibiting ac4C modification-mediated stability and upregulation. High YWHAH levels correlated with adverse outcomes and immune evasion in CRC patients, showing strong associations with immune checkpoint proteins and modest correlations with CD8 T cell infiltration. Co-culture experiments demonstrated YWHAH-induced CD8 T cell exhaustion, characterized by decreased proliferation and increased exhaustion markers. NAT10-mediated ac4C modification enhanced YWHAH stability in CRC. The involvement of YWHAH in CD8 + T cell exhaustion suggests its potential as a therapeutic target and prognostic marker in CRC immunotherapy, highlighting the intricate interplay between epitranscriptomic modifications, the tumor microenvironment, and immune responses in CRC progression.
Topics: Humans; Colorectal Neoplasms; CD8-Positive T-Lymphocytes; 14-3-3 Proteins; Cell Line, Tumor; Cytidine; Gene Expression Regulation, Neoplastic; Immune Checkpoint Inhibitors; T-Cell Exhaustion
PubMed: 38796965
DOI: 10.1016/j.intimp.2024.112317 -
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