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Clinical Cancer Research : An Official... Dec 2023Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.
PURPOSE
Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.
PATIENTS AND METHODS
We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma.
RESULTS
Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2).
CONCLUSIONS
Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.
Topics: Humans; Irinotecan; Gemcitabine; Pilot Projects; Fluorouracil; Liposomes; Pancreatic Neoplasms; Ergocalciferols; Antineoplastic Combined Chemotherapy Protocols; Leucovorin
PubMed: 37801295
DOI: 10.1158/1078-0432.CCR-23-1405 -
Science Advances Apr 2024Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with mutation still suffer...
Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.
Topics: Humans; Animals; Mice; Pyridoxine; Aldehyde Dehydrogenase; Seizures; Pyrimidines; Cognition; Epilepsy; 2-Aminoadipic Acid
PubMed: 38579001
DOI: 10.1126/sciadv.adl2764 -
Drug Metabolism Reviews 2024Severe acute respiratory syndrome 2 (SARS-CoV-2) caused the emergence of the COVID-19 pandemic all over the world. Several studies have suggested that antiviral drugs... (Review)
Review
Severe acute respiratory syndrome 2 (SARS-CoV-2) caused the emergence of the COVID-19 pandemic all over the world. Several studies have suggested that antiviral drugs such as favipiravir (FAV), remdesivir (RDV), and lopinavir (LPV) may potentially prevent the spread of the virus in the host cells and person-to-person transmission. Simultaneously with the widespread use of these drugs, their stability and action mechanism studies have also attracted the attention of many researchers. This review focuses on the action mechanism, metabolites and degradation products of these antiviral drugs (FAV, RDV and LPV) and demonstrates various methods for their quantification and discrimination in the different biological samples. Herein, the instrumental methods for analysis of the main form of drugs or their metabolite and degradation products are classified into two types: optical and chromatography methods which the last one in combination with various detectors provides a powerful method for routine and stability analyses. Some representative studies are reported in this review and the details of them are carefully explained. It is hoped that this review will be a good guideline study and provide a better understanding of these drugs from the aspects investigated in this study.
Topics: Pyrazines; Amides; Antiviral Agents; Adenosine Monophosphate; Humans; Alanine; Lopinavir; COVID-19 Drug Treatment; SARS-CoV-2; Animals
PubMed: 38445647
DOI: 10.1080/03602532.2024.2326415 -
Journal of the American Chemical Society Feb 2024Complex bacterial glycoconjugates drive interactions between pathogens, symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane...
Complex bacterial glycoconjugates drive interactions between pathogens, symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane interface by phosphoglycosyl transferases (PGTs), which catalyze the transfer of a phosphosugar from a soluble uridine diphosphosugar (UDP-sugar) substrate to a membrane-bound polyprenol-phosphate (Pren-P). The two distinct superfamilies of PGT enzymes (polytopic and monotopic) show striking differences in their structure and mechanism. We designed and synthesized a series of uridine bisphosphonates (UBPs), wherein the diphosphate of the UDP and UDP-sugar is replaced by a substituted methylene bisphosphonate (CXY-BPs; X/Y = F/F, Cl/Cl, ()-H/F, ()-H/F, H/H, CH/CH). UBPs and UBPs incorporating an -acetylglucosamine (GlcNAc) substituent at the β-phosphonate were evaluated as inhibitors of a polytopic PGT (WecA from ) and a monotopic PGT (PglC from ). Although CHF-BP most closely mimics diphosphate with respect to its acid/base properties, the less basic CF-BP conjugate more strongly inhibited PglC, whereas the more basic CH-BP analogue was the strongest inhibitor of WecA. These surprising differences indicate different modes of ligand binding for the different PGT superfamilies, implicating a modified P-O interaction with the structural Mg. For the monoPGT enzyme, the two diastereomeric CHF-BP conjugates, which feature a chiral center at the P-CHF-P carbon, also exhibited strikingly different binding affinities and the inclusion of GlcNAc with the native α-anomer configuration significantly improved binding affinity. UBP-sugars are thus revealed as informative new mechanistic probes of PGTs that may aid development of novel antibiotic agents for the exclusively prokaryotic monoPGT superfamily.
Topics: Humans; Transferases; Uridine; Diphosphates; Glycoconjugates; Diphosphonates; Sugars; Uridine Diphosphate
PubMed: 38271668
DOI: 10.1021/jacs.3c11402 -
Chemosphere Jun 2024As important components of soluble microbial products in water, nucleobases have attracted much attention due to the high toxicity of their direct aromatic halogenated...
As important components of soluble microbial products in water, nucleobases have attracted much attention due to the high toxicity of their direct aromatic halogenated disinfection by-products (AH-DBPs) during chlorination. However, multiple halogenation sites of AH-DBPs pose challenges to identify them. In this study, reaction sites of pyrimidine bases and nucleosides during chlorination were investigated by quantum chemical computational method. The results indicate that the anion salt forms play key roles in chlorination of uracil, thymine, and their nucleosides, while neutral forms make predominant contributions to cytosine and cytidine. In view of both kinetics and thermodynamics, C5 is the most reactive site for uracil and thymine, N3/C5 and N3 for respective uridine and thymidine, N1/C5/N and N for respective cytosine and cytidine, whose estimated apparent rate constants k of ∼10, 10/10, 10/10/10, and 10 M s, respectively, in consistent with the known experimental results. C6 in all pyrimidine compounds is hardly attacked by Cl in HOCl ascribed to its positive charge, but readily attacked by OH‾ in hydrolysis and the N1=C6 bond was found to possess the highest reactivity in hydrolysis among all double bonds. In addition, the structure-kinetic reactivity relationship study reveals a relatively strong correlation between lgk and APT charge in all pyrimidine compounds rather than FED (HOMO). The results are helpful to further understand the reactivity of various reaction sites in aromatic compounds during chlorination.
Topics: Halogenation; Pyrimidines; Nucleosides; Kinetics; Thermodynamics; Disinfection; Uracil; Water Pollutants, Chemical
PubMed: 38688350
DOI: 10.1016/j.chemosphere.2024.142189 -
Blood Advances Mar 2024Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine...
Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine-cytidine kinase 2 (UCK2), which supports vigorous proliferation. UCK2 catalyzes the monophosphorylation of cytidine/uridine and their analogues during pyrimidine biosynthesis and drug metabolism. We found that UCK2 was overexpressed aberrantly in HTLV-1-infected T cells but not in normal T cells. T-cell activation via T-cell receptor (TCR) signaling induced expression of UCK2 in normal T cells. Somatic alterations and epigenetic modifications in ATL cells activate TCR signaling. Therefore, we believe that expression of UCK2 in HTLV-1-infected cells is induced by dysregulated TCR signaling. Recently, we established azacitidine-resistant (AZA-R) cells showing absent expression of UCK2. AZA-R cells proliferated normally in vitro, whereas UCK2 knockdown inhibited ATL cell growth. Although uridine and cytidine accumulated in AZA-R cells, possibly because of dysfunction of pyrimidine salvage biosynthesis induced by loss of UCK2 expression, the amount of UTP and CTP was almost the same as in parental cells. Furthermore, AZA-R cells were more susceptible to an inhibitor of dihydroorotic acid dehydrogenase, which performs the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, and more resistant to dipyridamole, an inhibitor of pyrimidine salvage biosynthesis, suggesting that AZA-R cells adapt to UCK2 loss by increasing de novo pyrimidine nucleotide biosynthesis. Taken together, the data suggest that fine-tuning pyrimidine biosynthesis supports vigorous cell proliferation of both normal T cells and ATL cells.
Topics: Adult; Humans; Pyrimidines; Uridine; Cell Proliferation; Cytidine; Human T-lymphotropic virus 1; Pyrimidine Nucleotides; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 38190613
DOI: 10.1182/bloodadvances.2023011131 -
Lancet (London, England) Jun 2024Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains... (Randomized Controlled Trial)
Randomized Controlled Trial
Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.
BACKGROUND
Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population.
METHODS
This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing.
FINDINGS
Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group.
INTERPRETATION
Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma.
FUNDING
National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center.
TRANSLATION
For the Chinese translation of the abstract see Supplementary Materials section.
Topics: Humans; Middle Aged; Male; Female; Nasopharyngeal Carcinoma; Adult; China; Nasopharyngeal Neoplasms; Chemoradiotherapy; Antibodies, Monoclonal, Humanized; Induction Chemotherapy; Aged; Cisplatin; Antineoplastic Combined Chemotherapy Protocols; Gemcitabine; Deoxycytidine; Young Adult; Adolescent; Progression-Free Survival
PubMed: 38824941
DOI: 10.1016/S0140-6736(24)00594-4 -
Cell Reports May 2024Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis due to therapeutic resistance. We show that PDAC cells undergo global epigenetic reprogramming to...
Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis due to therapeutic resistance. We show that PDAC cells undergo global epigenetic reprogramming to acquire chemoresistance, a process that is driven at least in part by protein arginine methyltransferase 1 (PRMT1). Genetic or pharmacological PRMT1 inhibition impairs adaptive epigenetic reprogramming and delays acquired resistance to gemcitabine and other common chemo drugs. Mechanistically, gemcitabine treatment induces translocation of PRMT1 into the nucleus, where its enzymatic activity limits the assembly of chromatin-bound MAFF/BACH1 transcriptional complexes. Cut&Tag chromatin profiling of H3K27Ac, MAFF, and BACH1 suggests a pivotal role for MAFF/BACH1 in global epigenetic response to gemcitabine, which is confirmed by genetically silencing MAFF. PRMT1 and MAFF/BACH1 signature genes identified by Cut&Tag analysis distinguish gemcitabine-resistant from gemcitabine-sensitive patient-derived xenografts of PDAC, supporting the PRMT1-MAFF/BACH1 epigenetic regulatory axis as a potential therapeutic avenue for improving the efficacy and durability of chemotherapies in patients of PDAC.
Topics: Protein-Arginine N-Methyltransferases; Humans; Drug Resistance, Neoplasm; Epigenesis, Genetic; Pancreatic Neoplasms; Gemcitabine; Deoxycytidine; Repressor Proteins; Cell Line, Tumor; Animals; Mice; Carcinoma, Pancreatic Ductal; Gene Expression Regulation, Neoplastic; Cellular Reprogramming
PubMed: 38691454
DOI: 10.1016/j.celrep.2024.114176 -
PloS One 2024Hypertrophic Cardiomyopathy (HCM) is a complex cardiac condition characterized by hypercontractility of cardiac muscle leading to a dynamic obstruction of left... (Meta-Analysis)
Meta-Analysis
Evaluating the efficacy and safety of mavacamten in hypertrophic cardiomyopathy: A systematic review and meta-analysis focusing on qualitative assessment, biomarkers, and cardiac imaging.
BACKGROUND
Hypertrophic Cardiomyopathy (HCM) is a complex cardiac condition characterized by hypercontractility of cardiac muscle leading to a dynamic obstruction of left ventricular outlet tract (LVOT). Mavacamten, a first-in-class cardiac myosin inhibitor, is increasingly being studied in randomized controlled trials. In this meta-analysis, we aimed to analyse the efficacy and safety profile of Mavacamten compared to placebo in patients of HCM.
METHOD
We carried out a comprehensive search in PubMed, Cochrane, and clinicaltrials.gov to analyze the efficacy and safety of mavacamten compared to placebo from 2010 to 2023. To calculate pooled odds ratio (OR) or risk ratio (RR) at 95% confidence interval (CI), the Mantel-Haenszel formula with random effect was used and Generic Inverse Variance method assessed pooled mean difference value at a 95% CI. RevMan was used for analysis. P<0.05 was considered significant.
RESULTS
We analyzed five phase 3 RCTs including 609 patients to compare mavacamten with a placebo. New York Heart Association (NYHA) grade improvement and KCCQ score showed the odds ratio as 4.94 and 7.93 with p<0.00001 at random effect, respectively. Cardiac imaging which included LAVI, LVOT at rest, LVOT post valsalva, LVOT post-exercise, and reduction in LVEF showed the pooled mean differences for change as -5.29, -49.72, -57.45, -36.11, and -3.00 respectively. Changes in LVEDV and LVMI were not statistically significant. The pooled mean difference for change in NT-proBNP and Cardiac troponin-I showed 0.20 and 0.57 with p<0.00001. The efficacy was evaluated in 1) A composite score, which was defined as either 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction, or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening and 2) changes in pVO2, which was not statistically significant. Similarly, any treatment-associated emergent adverse effects (TEAE), treatment-associated serious adverse effects (TSAE), and cardiac-related adverse effects were not statistically significant.
CONCLUSION
Mavacamten influences diverse facets of HCM comprehensively. Notably, our study delved into the drug's impact on the heart's structural and functional aspects, providing insights that complement prior findings. Further large-scale trials are needed to evaluate the safety profile of Mavacamten.
Topics: Humans; Cardiomyopathy, Hypertrophic; Heart; Benzylamines; Biomarkers; Uracil
PubMed: 38635724
DOI: 10.1371/journal.pone.0301704 -
Photochemical & Photobiological... Feb 2024Fluorescent nucleobase and nucleic acid analogs are important tools in chemical and molecular biology as fluorescent labelling of nucleobases has applications in...
Fluorescent nucleobase and nucleic acid analogs are important tools in chemical and molecular biology as fluorescent labelling of nucleobases has applications in cellular imaging and anti-tumor activity. Boron-dipyrromethene (BODIPY) dyes exhibiting high brightness and good photostability are extensively used as fluorescent labelling agents and as type II photosensitizers for photodynamic therapy. Thus, the combination of nucleobases and BODIPY to obtain new compounds with both anti-tumor activity and fluorescent imaging functions is the focus of our research. We synthesized two new nucleobase analogs 1 and 2 by fusing the BODIPY core directly with uracil which resulted in favorable photophysical properties and high emission quantum efficiencies particularly in organic solvents. Further, we explored the newly synthesized derivatives, which possessed good singlet oxygen generation efficiencies and bio-compatibility, as potential PDT agents and our results show that they exhibit in vitro anti-tumor activities.
Topics: Humans; Uracil; Photosensitizing Agents; Boron Compounds; Singlet Oxygen; Neoplasms; Fluorescent Dyes; Photochemotherapy
PubMed: 38227134
DOI: 10.1007/s43630-023-00524-z