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Digestive Diseases and Sciences Jun 2024Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies...
BACKGROUND AND AIMS
Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies (ADAs). An immunomodulator (IMM) used in combination with initial IFX induction is known to reduce ADA development and improve clinical outcomes. We aimed to assess the impact of reactively adding an IMM to patients on IFX monotherapy.
METHODS
We conducted a retrospective cohort study and systematic review with meta-analysis of patients with IBD demonstrating immunologic LOR, with or without clinical LOR, that had an IMM (azathioprine, 6-mercaptopurine, or methotrexate) reactively added (reactive combination therapy; rCT) to combat elevated ADAs and raise IFX level. Data were extracted for pooled effect size estimation using random-effects models, and ADA and IFX trough levels were compared pre- and post-IMM initiation.
RESULTS
We identified 6 patients who received rCT due to rising ADA titers and low IFX levels. Median ADA titer decreased from 506 ng/mL (interquartile range (IQR) [416-750]) to 76.5 ng/mL (IQR [25.8-232]), an 85% decrease (p = 0.031). Median IFX trough increased from 0.4 µg/mL (IQR [0.4-0.48]) to 8.25 µg/mL (IQR [3.7-9.6]), a 20.6-fold increase (p = 0.038). Meta-analysis pooled effect size of 7 studies with 89 patients showed an 87% ADA titer reduction [95% confidence interval (CI) = 72-94%], 6.7-fold increased IFX trough (95% CI = 2.4-18.7), and 76% clinical remission rescue rate (95% CI = 59-93%).
CONCLUSIONS
These results suggest rCT is a valid rescue strategy in patients with immunogenic LOR to IFX to reduce ADA titers, restore therapeutic IFX levels, and recapture clinical remission of IBD.
PubMed: 38877332
DOI: 10.1007/s10620-024-08515-5 -
Biochemical Pharmacology Jun 2024Methylation is a vital chemical reaction in the metabolism of many drugs, neurotransmitters, hormones, and exogenous compounds. Among them, S-methylation plays a... (Review)
Review
Methylation is a vital chemical reaction in the metabolism of many drugs, neurotransmitters, hormones, and exogenous compounds. Among them, S-methylation plays a significant role in the biotransformation of sulfur-containing compounds, particularly chemicals with sulfhydryl groups. Currently, only three S-methyltransferases have been reported: thiopurine methyltransferase (TPMT), thiol methyltransferase (TMT), and thioether methyltransferase (TEMT). These enzymes are involved in various biological processes such as gene regulation, signal transduction, protein repair, tumor progression, and biosynthesis and degradation reactions in animals, plants, and microorganisms. Furthermore, they play pivotal roles in the metabolic pathways of essential drugs and contribute to the advancement of diseases such as tumors. This paper reviews the research progress on relevant structural features, metabolic mechanisms, inhibitor development, and influencing factors (gene polymorphism, S-adenosylmethionine level, race, sex, age, and disease) of S-methyltransferases. We hope that a better comprehension of S-methyltransferases will help to provide a reference for the development of novel strategies for related disorders and improve long-term efficacy.
PubMed: 38876259
DOI: 10.1016/j.bcp.2024.116361 -
Chemical Science Jun 2024Surface-protecting ligands, as a major component of metal nanoclusters (MNCs), can dominate molecular characteristics, performance behaviors, and biological properties...
Surface-protecting ligands, as a major component of metal nanoclusters (MNCs), can dominate molecular characteristics, performance behaviors, and biological properties of MNCs, which brings diversity and flexibility to the nanoclusters and largely promotes their applications in optics, electricity, magnetism, catalysis, biology, and other fields. We report herein the design of a new kind of water-soluble luminescent gold nanoclusters (AuNCs) for enzyme-activatable charge transfer (CT) based on the ligand engineering of AuNCs with 6-mercaptopurine ribonucleoside (MPR). This elaborately designed cluster, Au(MPR), can form a stable intramolecular CT state after light excitation, and exhibits long-lived color-tunable phosphorescence. After the cleavage by purine nucleoside phosphorylase (PNP), the CT triplet state can be easily directed to a low-lying energy level, leading to a bathochromic shift of the emission band accompanied by weaker and shorter-lived luminescence. Remarkably, these ligand-engineered AuNCs show high affinity towards PNP as well as decent performance for analyzing and visualizing enzyme activity and related drugs. The work of this paper provides a good example for diversifying physicochemical properties and application scenarios of MNCs by rational ligand engineering, which will facilitate future interest and new strategies to precisely engineer solution-based nanocluster materials.
PubMed: 38873061
DOI: 10.1039/d4sc01509f -
Scientific Reports Jun 2024Paneth cells (PCs), a subset of intestinal epithelial cells (IECs) found at the base of small intestinal crypts, play an essential role in maintaining intestinal...
Paneth cells (PCs), a subset of intestinal epithelial cells (IECs) found at the base of small intestinal crypts, play an essential role in maintaining intestinal homeostasis. Altered PCs function is associated with diverse intestinal pathologies, including ileal Crohn's disease (CD). CD patients with ileal involvement have been previously demonstrated to display impairment in PCs and decreased levels of anti-microbial peptides. Although the immunosuppressive drug Azathioprine (AZA) is widely used in CD therapy, the impact of AZA on IEC differentiation remains largely elusive. In the present study, we hypothesized that the orally administered drug AZA also exerts its effect through modulation of the intestinal epithelium and specifically via modulation of PC function. AZA-treated CD patients exhibited an ileal upregulation of AMPs on both mRNA and protein levels compared to non-AZA treated patients. Upon in vitro AZA stimulation, intestinal epithelial cell line MODE-K exhibited heightened expression levels of PC marker in concert with diminished cell proliferation but boosted mitochondrial OXPHOS activity. Moreover, differentiation of IECs, including PCs differentiation, was boosted in AZA-treated murine small intestinal organoids and was associated with decreased D-glucose consumption and decreased growth rates. Of note, AZA treatment strongly decreased Lgr5 mRNA expression as well as Ki67 positive cells. Further, AZA restored dysregulated PCs associated with mitochondrial dysfunction. AZA-dependent inhibition of IEC proliferation is accompanied by boosted mitochondria function and IEC differentiation into PC.
Topics: Crohn Disease; Azathioprine; Paneth Cells; Humans; Cell Differentiation; Animals; Mice; Intestinal Mucosa; Female; Male; Ileum; Adult; Organoids; Epithelial Cells; Cell Proliferation; Middle Aged; Cell Line; Severity of Illness Index
PubMed: 38839896
DOI: 10.1038/s41598-024-63730-4 -
Therapeutic Advances in Hematology 2024Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed.
BACKGROUND
Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed.
OBJECTIVES
To summarize the outcome of our new treatment strategies for pediatric AML, which is characterized by dual induction and acute lymphoblastic leukemia (ALL) elements consolidation.
DESIGN
Retrospective, single-arm study.
METHODS
From July 2012 to December 2019, an intensive chemotherapy protocol was used for newly diagnosed children with AML, which contains dual induction, three courses of consolidations based on high-dose cytarabine, and two courses of consolidations composed of high-dose methotrexate, vincristine, asparaginase, and mercaptopurine (ALL-like elements). Blasts were monitored by bone marrow smears at intervals, and two lumbar punctures were performed during chemotherapy. We retrospectively analyzed the efficacy and safety of this study. The last follow-up was on 26 May 2023.
RESULTS
A total of 70 pediatric AMLs were included. The median age at diagnosis was 6.7 (0.5-16.0) years. The median initial WBC count was 23.74 × 10/L, 11 of whom ⩾100 × 10/L. After dual induction, there were 62 cases of complete remission (CR), 5 cases of partial remission, and 3 cases of nonremission. The CR rate was 88.57%. The median follow-up time was 5.8 (0.2-9.4) years, the 5-year overall survival was 78.2% ± 5%, the event-free survival (EFS) was 71.2% ± 5.6%, and the cumulative recurrence rate was 27.75%. The 5-year EFS of patients with initial WBC < 100 × 10/L ( = 59) and ⩾100 × 10/L ( = 11) were 76.4% ± 5.7% and 45.5% ± 15% ( = 0.013), respectively. A total of 650 hospital infections occurred. The main causes of infection were respiratory tract infection (26.92%), septicemia (18.46%), stomatitis (11.85%), and skin and soft-tissue infection (10.46%).
CONCLUSION
This intensive treatment protocol with dual induction and ALL-like elements is effective and safe for childhood AML. Initial WBC ⩾ 100 × 10/L was the only independent risk factor in this cohort.
TRIAL REGISTRATION
It is a retrospective study, and no registration on ClinicalTrials.gov.
PubMed: 38828002
DOI: 10.1177/20406207241256894 -
Spectrochimica Acta. Part A, Molecular... Oct 20246-mercaptopurine (6-MP) is widely used in the treatment of many diseases, but exhibits some serious side effects due to its toxicity. Therefore, it is important and...
6-mercaptopurine (6-MP) is widely used in the treatment of many diseases, but exhibits some serious side effects due to its toxicity. Therefore, it is important and imperative to effectively control and monitoring concentration of 6-MP. Herein, we designed a smartphone-assisted colorimetric sensing platform for 6-MP detection, based on an excellent β-cyclodextrin modified MnO nanosheets (β-CD@MnO NNS) mediated oxidase-like activity. β-CD@MnO NNS can directly oxidizes 3,3',5,5'-tetramethylbenzidine (TMB) into oxidized TMB with color changes, yielding more than 3-fold higher oxidase-like catalytic activity compared with individual MnO NNS. After adding 6-MP, β-CD@MnO NNS can be reduced to Mn and lose their oxidase-like properties, resulting in a color and absorbance change for sensitive and selectivity detection of 6-MP. Meanwhile, the smartphone-based color recognition application can intuitively and simply measure the concentration of 6-MP. The limits of detection UV-vis instrument and smartphone were 0.35 μM and 0.86 μM, respectively. This method has also been successfully applied to the detection of real samples. Finally, this study provides a new promising platform for detection of 6-MP and is expected to be used in application of pharmaceutical analysis and biomedicine.
Topics: Colorimetry; Manganese Compounds; beta-Cyclodextrins; Oxides; Smartphone; Mercaptopurine; Nanostructures; Oxidoreductases; Limit of Detection; Humans; Benzidines
PubMed: 38796891
DOI: 10.1016/j.saa.2024.124493 -
Molecules (Basel, Switzerland) May 2024The rapid advancements in nanotechnology in the field of nanomedicine have the potential to significantly enhance therapeutic strategies for cancer treatment. There is... (Review)
Review
The rapid advancements in nanotechnology in the field of nanomedicine have the potential to significantly enhance therapeutic strategies for cancer treatment. There is considerable promise for enhancing the efficacy of cancer therapy through the manufacture of innovative nanocomposite materials. Metallic nanoparticles have been found to enhance the release of anticancer medications that are loaded onto them, resulting in a sustained release, hence reducing the dosage required for drug administration and preventing their buildup in healthy cells. The combination of nanotechnology with biocompatible materials offers new prospects for the development of advanced therapies that exhibit enhanced selectivity, reduced adverse effects, and improved patient outcomes. Chitosan (CS), a polysaccharide possessing distinct physicochemical properties, exhibits favorable attributes for controlled drug delivery due to its biocompatibility and biodegradability. Chitosan nanocomposites exhibit heightened stability, improved biocompatibility, and prolonged release characteristics for anticancer medicines. The incorporation of gold (Au) nanoparticles into the chitosan nanocomposite results in the manifestation of photothermal characteristics, whereas the inclusion of silver (Ag) nanoparticles boosts the antibacterial capabilities of the synthesized nanocomposite. The objective of this review is to investigate the recent progress in the utilization of Ag and Au nanoparticles, or a combination thereof, within a chitosan matrix or its modified derivatives for the purpose of anticancer drug delivery. The research findings for the potential of a chitosan nanocomposite to deliver various anticancer drugs, such as doxorubicin, 5-Fluroacil, curcumin, paclitaxel, and 6-mercaptopurine, were investigated. Moreover, various modifications carried out on the chitosan matrix phase and the nanocomposite surfaces to enhance targeting selectivity, loading efficiency, and pH sensitivity were highlighted. In addition, challenges and perspectives that could motivate further research related to the applications of chitosan nanocomposites in cancer therapy were summarized.
Topics: Chitosan; Nanocomposites; Antineoplastic Agents; Silver; Humans; Metal Nanoparticles; Gold; Drug Delivery Systems; Drug Carriers; Neoplasms; Animals
PubMed: 38792255
DOI: 10.3390/molecules29102393 -
BMC Medical Genomics May 2024Therapy with anti-cancer drugs remain the cornerstone of treating cancer. The effectiveness and safety of anti-cancer drugs vary significantly among individuals due to...
BACKGROUND
Therapy with anti-cancer drugs remain the cornerstone of treating cancer. The effectiveness and safety of anti-cancer drugs vary significantly among individuals due to genetic factors influencing the drug response and metabolism. Data on the pharmacogenomic variations in Sri Lankans related to anti-cancer therapy is sparse. As current treatment guidelines in Sri Lanka often do not consider local pharmacogenomic variants, this study aimed to explore the diversity of pharmacogenomic variants in the Sri Lankan population to pave the way for personalized treatment approaches and improve patient outcomes.
METHODS
Pharmacogenomic data regarding variant-drug pairs of genes CYP2D6, DPYD, NUDT15, EPAS1, and XRCC1 with clinical annotations labelled as evidence levels 1A-2B were obtained from the Pharmacogenomics Knowledgebase database. Their frequencies in Sri Lankans were obtained from an anonymized database that was derived from 541 Sri Lankans who underwent exome sequencing at the Human Genetics Unit, Faculty of Medicine, University of Colombo. Variations in DPYD, NUDT15, and EPAS1 genes are related to increased toxicity to fluoropyrimidines, mercaptopurines, and sorafenib respectively. Variations in CYP2D6 and XRCC1 genes are related to changes in efficacy of tamoxifen and platinum compounds, respectively. Minor allele frequencies of these variants were calculated and compared with other populations.
RESULTS
MAFs of rs1065852 c.100 C > T (CYP2D6), rs3918290 c.1905 + 1G > A (DPYD), rs56038477 c.1236G > A (DPYD), rs7557402 c.1035-7 C > G (EPAS1), rs116855232 c.415 C > T (NUDT15*3), and rs25487 c.1196 A > G (XRCC1) were: 12.9% [95%CI:10.9-14.9], 1.5% [95%CI:0.8-2.2], 1.2% [95%CI:0.5-1.8], 37.7% [95%CI:34.8-40.6], 8.3% [95%CI:6.7-10.0], and 64.0% [95%CI:61.1-66.8], respectively. Frequencies of rs1065852 c.100 C > T (CYP2D6), rs7557402 c.1035-7 C > G (EPAS1), and rs25487 (XRCC1) were significantly lower in Sri Lankans, while frequencies of rs116855232 c.415 C > T (NUDT15*3) and rs56038477 c.1236G > A (DPYD) were significantly higher in Sri Lankans when compared to some Western and Asian populations.
CONCLUSION
Sri Lankans are likely to show lower toxicity risk with sorafenib (rs7557402 c.84,131 C > G) and, higher toxicity risk with fluoropyrimidines (rs56038477 c.1236G > A) and mercaptopurine (rs116855232 c.415 C > T), and reduced effectiveness with tamoxifen (rs1065852 c.100 C > T) and platinum compounds (rs25487). These findings highlight the potential contribution of these genetic variations to the individual variability in anti-cancer dosage requirements among Sri Lankans.
Topics: Humans; Sri Lanka; Antineoplastic Agents; Pharmacogenomic Variants; X-ray Repair Cross Complementing Protein 1; Pyrophosphatases; Basic Helix-Loop-Helix Transcription Factors; Cytochrome P-450 CYP2D6; Neoplasms; Asian People; Pharmacogenetics; Gene Frequency; Nudix Hydrolases
PubMed: 38789983
DOI: 10.1186/s12920-024-01919-2 -
Journal of Pediatric Hematology/oncology Jul 2024Thiopurine-methyltransferase (TPMT) and nudix-hydrolase-15 (NUDT15) are enzymes relevant to the metabolism of thiopurine medications, used to treat immunologic disorders...
Thiopurine-methyltransferase (TPMT) and nudix-hydrolase-15 (NUDT15) are enzymes relevant to the metabolism of thiopurine medications, used to treat immunologic disorders and malignancies. Standard dosing administered in the setting of TPMT/NUDT15 dysfunction can cause excessive cytotoxic metabolites and life-threatening complications. We describe an adolescent with high-risk B-cell acute lymphoblastic leukemia (ALL) whose TPMT/NUDT15 status was unknown due to lack of insurance approval for genetic testing. He subsequently developed myelosuppression and severe veno-occlusive disease (VOD) after receiving 6-mercaptopurine (6-MP). Our patient provides an example of a very rare 6-MP-related toxicity and the potential benefit of TPMT/NUDT15 screening before initiating thiopurine therapy.
Topics: Humans; Mercaptopurine; Male; Hepatic Veno-Occlusive Disease; Adolescent; Antimetabolites, Antineoplastic; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Methyltransferases
PubMed: 38775421
DOI: 10.1097/MPH.0000000000002883 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Jun 2024
Topics: Humans; Male; Adolescent; Colitis, Ulcerative; Ustekinumab; Antibodies, Monoclonal, Humanized; Infliximab; Drug Therapy, Combination; Mesalamine; Treatment Outcome; Venous Thrombosis; Immunosuppressive Agents; Azathioprine
PubMed: 38763883
DOI: 10.3760/cma.j.cn112140-20230928-00232