-
Biochemistry Jun 2024OxaD is a flavin-dependent monooxygenase (FMO) responsible for catalyzing the oxidation of an indole nitrogen atom, resulting in the formation of a nitrone. Nitrones...
OxaD is a flavin-dependent monooxygenase (FMO) responsible for catalyzing the oxidation of an indole nitrogen atom, resulting in the formation of a nitrone. Nitrones serve as versatile intermediates in complex syntheses, including challenging reactions like cycloadditions. Traditional organic synthesis methods often yield limited results and involve environmentally harmful chemicals. Therefore, the enzymatic synthesis of nitrone-containing compounds holds promise for more sustainable industrial processes. In this study, we explored the catalytic mechanism of OxaD using a combination of steady-state and rapid-reaction kinetics, site-directed mutagenesis, spectroscopy, and structural modeling. Our investigations showed that OxaD catalyzes two oxidations of the indole nitrogen of roquefortine C, ultimately yielding roquefortine L. The reductive-half reaction analysis indicated that OxaD rapidly undergoes reduction and follows a "cautious" flavin reduction mechanism by requiring substrate binding before reduction can take place. This characteristic places OxaD in class A of the FMO family, a classification supported by a structural model featuring a single Rossmann nucleotide binding domain and a glutathione reductase fold. Furthermore, our spectroscopic analysis unveiled both enzyme-substrate and enzyme-intermediate complexes. Our analysis of the oxidative-half reaction suggests that the flavin dehydration step is the slow step in the catalytic cycle. Finally, through mutagenesis of the conserved D63 residue, we demonstrated its role in flavin motion and product oxygenation. Based on our findings, we propose a catalytic mechanism for OxaD and provide insights into the active site architecture within class A FMOs.
Topics: Nitrogen Oxides; Oxidation-Reduction; Mixed Function Oxygenases; Kinetics; Mutagenesis, Site-Directed; Flavins; Models, Molecular; Bacterial Proteins; Oxygenases
PubMed: 38779817
DOI: 10.1021/acs.biochem.3c00656 -
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 -
Oncology (Williston Park, N.Y.) May 2024Determining treatment options for patients with locally advanced rectal cancer after the PROSPECT trial data readout adds an important level to the decision-making...
Determining treatment options for patients with locally advanced rectal cancer after the PROSPECT trial data readout adds an important level to the decision-making process.
Topics: Humans; Rectal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Randomized Controlled Trials as Topic; Leucovorin
PubMed: 38776515
DOI: 10.46883/2024.25921019 -
RMD Open May 2024Non-adherence to rheumatoid arthritis (RA) treatments must be identified. A methotrexate (MTX) urinary dosage (METU) was recently developed. The aim of our study was to...
OBJECTIVES
Non-adherence to rheumatoid arthritis (RA) treatments must be identified. A methotrexate (MTX) urinary dosage (METU) was recently developed. The aim of our study was to assess adherence to MTX in RA using METU in real-life conditions and to compare it with indirect adherence measurement technics.
METHODS
We performed a cross-sectional study at Reims University Hospital. We included over 18-year-old patients with RA treated by MTX for more than 6 months. Patients were invited to complete demographic, clinical and psychological questionnaires and adherence measurement technics (Compliance Questionnaire of Rheumatology (CQR) and Medication Possession Ratio (MPR)). A urinary sample was collected to measure MTX and information about tolerance was evaluated through Methotrexate Intolerance Severity Score.
RESULTS
84 patients were included, 26 using oral MTX, 58 subcutaneous (SC) MTX. Among them, 73% were female, mean age was 61.5 years, MTX mean dose was 15 mg/week and 61.9% were treated by biological DMARDs (Disease Modifying Antirheumatic Drugs). 77 patients (91.7%) were adherent to treatment according to METU, whereas MPR and CQR reported less adherence (69.5% and 61.9%, respectively). MPR and METU were not significantly different in SC MTX users (p=0.059). Non-adherent patients had a higher number of tender joints and C reactive protein value (p<0.05).
CONCLUSION
This is the first largest study evaluating MTX adherence in patients with RA using a urinary dosage. We identified that indirect adherence measurements did not reflect real-life adherence. It would be appreciable to realise METU, in a new study, in patients with RA with unexplained response to treatment, to consider it before escalating therapeutic strategy.
Topics: Humans; Arthritis, Rheumatoid; Methotrexate; Female; Male; Medication Adherence; Antirheumatic Agents; Cross-Sectional Studies; Middle Aged; Aged; Surveys and Questionnaires; Adult; Biomarkers
PubMed: 38772677
DOI: 10.1136/rmdopen-2023-004024 -
Journal of Animal Science Jan 2024The objective of this study was to determine the dose-dependent response of one-carbon metabolite (OCM: methionine, choline, folate, and vitamin B12) supplementation on...
The objective of this study was to determine the dose-dependent response of one-carbon metabolite (OCM: methionine, choline, folate, and vitamin B12) supplementation on heifer dry matter intake on fixed gain, organ mass, hematology, cytokine concentration, pancreatic and jejunal enzyme activity, and muscle hydrogen peroxide production. Angus heifers (n = 30; body weight [BW] = 392.6 ± 12.6 kg) were individually fed and assigned to one of five treatments: 0XNEG: total mixed ration (TMR) and saline injections at days 0 and 7 of the estrous cycle, 0XPOS: TMR, rumen-protected methionine (MET) fed at 0.08% of the diet dry matter, rumen-protected choline (CHOL) fed at 60 g/d, and saline injections at days 0 and 7, 0.5X: TMR, MET, CHOL, 5-mg B12, and 80-mg folate injections at days 0 and 7, 1X: TMR, MET CHOL, 10-mg vitamin B12, and 160-mg folate at days 0 and 7, and 2X: TMR, MET, CHOL, 20-mg vitamin B12, and 320-mg folate at days 0 and 7. All heifers were estrus synchronized but not bred, and blood samples were collected on days 0, 7, and at slaughter (day 14) during which tissues were collected. By design, heifer ADG did not differ (P = 0.96). Spleen weight and uterine weight were affected cubically (P = 0.03) decreasing from 0XPOS to 0.5X. Ovarian weight decreased linearly (P < 0.01) with increasing folate and B12 injection. Hemoglobin and hematocrit percentage were decreased (P < 0.01) in the 0.5X treatment compared with all other treatments. Plasma glucose, histotroph protein, and pancreatic α-amylase were decreased (P ≤ 0.04) in the 0.5X treatment. Heifers on the 2X treatment had greater pancreatic α-amylase compared with 0XNEG and 0.5X treatment. Interleukin-6 in plasma tended (P = 0.08) to be greater in the 0XPOS heifers compared with all other treatments. Lastly, 0XPOS-treated heifers had reduced (P ≤ 0.07) hydrogen peroxide production in muscle compared with 0XNEG heifers. These data imply that while certain doses of OCM do not improve whole animal physiology, OCM supplementation doses that disrupt one-carbon metabolism, such as that of the 0.5X treatment, can induce a negative systemic response that results in negative effects in both the dam and the conceptus during early gestation. Therefore, it is necessary to simultaneously establish an optimal OCM dose that increases circulating concentrations for use by the dam and the conceptus, while avoiding potential negative side effects of a disruptive OCM, to evaluate the long-term impacts of OCM supplementation of offspring programming.
Topics: Animals; Female; Cattle; Methionine; Dietary Supplements; Diet; Vitamin B 12; Folic Acid; Animal Feed; Choline
PubMed: 38770669
DOI: 10.1093/jas/skae144 -
Indian Journal of Ophthalmology Jul 2024This study aimed to report the long-term results of combined topography-guided photorefractive keratectomy (PRK) and accelerated corneal collagen cross-linking (CXL) for...
PURPOSE
This study aimed to report the long-term results of combined topography-guided photorefractive keratectomy (PRK) and accelerated corneal collagen cross-linking (CXL) for keratoconus using the Zeiss refractive coordinated system.
METHODS
A prospective interventional study was conducted in a tertiary eye care hospital in South India. Patients with mild-to-moderate progressive keratoconus and corneal pachymetry greater than 450 µm were included. They underwent customized topography-guided PRK followed by CXL. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and keratometry readings and complications were evaluated at 1, 3, 6, 12, and 24 months postoperatively.
RESULTS
Thirty patients (30 eyes) were included in the study. All study parameters showed a statistically significant improvement postoperatively over baseline values. At 24 months, the mean UDVA improved from 0.8 ± 0.180 logarithm of the minimum angle of resolution (logMAR) to 0.38 ± 0.118 logMAR ( P -value <0.001) and CDVA improved from 0.467 ± 0.142 logMAR to 0.227 ± 0.078 logMAR ( P -value <0.001). The mean flat, steep, and maximum keratometry values were significantly reduced by 2.133, 3, and 4.54 diopters, respectively, at the last follow-up examination ( P -value <0.001).
CONCLUSION
The combined topography-guided PRK and accelerated CXL procedure seem to be a promising treatment alternative for early keratoconus. This is the first such study on the Zeiss refractive coordinated system. However, further studies with a larger study population and longer follow-up periods are required to draw final conclusions about the benefits of this procedure in keratoconus.
Topics: Humans; Photorefractive Keratectomy; Keratoconus; Corneal Topography; Male; Prospective Studies; Female; Photosensitizing Agents; Collagen; Cross-Linking Reagents; Visual Acuity; Adult; Young Adult; Photochemotherapy; Riboflavin; Refraction, Ocular; Follow-Up Studies; Lasers, Excimer; Ultraviolet Rays; Surgery, Computer-Assisted; Cornea; Adolescent; Corneal Stroma; Treatment Outcome; Combined Modality Therapy
PubMed: 38767551
DOI: 10.4103/IJO.IJO_791_23 -
International Journal of Nanomedicine 2024Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that involves synovitis, cartilage destruction, and even joint damage. Traditional agents used for...
INTRODUCTION
Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that involves synovitis, cartilage destruction, and even joint damage. Traditional agents used for RA therapy remain unsatisfactory because of their low efficiency and obvious adverse effects. Therefore, we here established RA microenvironment-responsive targeted micelles that can respond to the increase in reactive oxygen species (ROS) levels in the joint and improve macrophage-specific targeting of loaded drugs.
METHODS
We here prepared ROS-responsive folate-modified curcumin micelles (TK-FA-Cur-Ms) in which thioketal (TK) was used as a ROS-responsive linker for modifying polyethylene glycol 5000 (PEG) on the micellar surface. When micelles were in the ROS-overexpressing inflammatory microenvironment, the PEG hydration layer was shed, and the targeting ligand FA was exposed, thereby enhancing cellular uptake by macrophages through active targeting. The targeting, ROS sensitivity and anti-inflammatory properties of the micelles were assessed in vitro. Collagen-induced arthritis (CIA) rats model was utilized to investigate the targeting, expression of serum inflammatory factors and histology change of the articular cartilage by micelles in vivo.
RESULTS
TK-FA-Cur-Ms had a particle size of 90.07 ± 3.44 nm, which decreased to 78.87 ± 2.41 nm after incubation with HO. The micelles exhibited in vitro targeting of RAW264.7 cells and significantly inhibited inflammatory cytokine levels. Pharmacodynamic studies have revealed that TK-FA-Cur-Ms prolonged the drug circulation and exhibited augmented cartilage-protective and anti-inflammatory effects in vivo.
CONCLUSION
The unique ROS-responsive targeted micelles with targeting, ROS sensitivity and anti-inflammatory properties were successfully prepared and may offer an effective therapeutic strategy against RA.
Topics: Animals; Micelles; Curcumin; Reactive Oxygen Species; Rats; Arthritis, Rheumatoid; RAW 264.7 Cells; Mice; Folic Acid; Arthritis, Experimental; Polyethylene Glycols; Drug Carriers; Folate Receptors, GPI-Anchored; Macrophages; Male; Particle Size; Anti-Inflammatory Agents; Disease Models, Animal
PubMed: 38766660
DOI: 10.2147/IJN.S458957 -
Frontiers in Immunology 2024Corticosteroid therapy is the mainstay of immune effector cell-associated neurotoxicity syndrome (ICANS) management, although its use has been associated with worse...
Corticosteroid therapy is the mainstay of immune effector cell-associated neurotoxicity syndrome (ICANS) management, although its use has been associated with worse overall survival (OS) and progression-free survival (PFS) after chimeric antigen receptor T-cell (CAR-T cell) therapy. Many options are being investigated for prophylaxis and management. Accumulating evidence supports the use of intrathecal (IT) chemotherapy for the management of high-grade ICANS. Here, we describe a case of a patient with stage IV Primary mediastinal B-cell lymphoma (PMBCL) successfully treated with IT methotrexate, cytarabine, and dexamethasone as first-line therapy for CD19 CAR-T cell-associated grade IV ICANS. The stable and rapid resolution of ICANS to grade 0 allowed us to discontinue systemic corticosteroid use, avoiding CAR-T cells ablation and ensuring preservation of CAR-T cell function. The described patient achieved a complete radiologic and clinical response to CD19 CAR-T cell therapy and remains disease-free after 9 months. This case demonstrates a promising example of how IT chemotherapy could be used as first-line treatment for the management of high-grade ICANS.
Topics: Humans; Dexamethasone; Injections, Spinal; Methotrexate; Cytarabine; Antineoplastic Combined Chemotherapy Protocols; Male; Neurotoxicity Syndromes; Middle Aged; Treatment Outcome; Immunotherapy, Adoptive; Lymphoma, B-Cell; Female
PubMed: 38765003
DOI: 10.3389/fimmu.2024.1380451 -
Complementary Therapies in Medicine Jun 2024The purpose of this systematic review was to examine the association between folic acid supplementation during pregnancy and the risk of preeclampsia. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The purpose of this systematic review was to examine the association between folic acid supplementation during pregnancy and the risk of preeclampsia.
METHODS
Relevant studies were included by searching Embase, PubMed, Scope, Web of science, Cochrane Library databases. Studies were reviewed according to prespecified inclusion and exclusion criteria. Study characteristics were summarized, and study quality was assessed. Risk ratios (RR) and 95% confidence intervals (CI) were used as indicators of effect to assess the relationship between folic acid supplementation and risk of preeclampsia.
RESULTS
The protocol of this study was prospectively registered with the PROSPERO (registration No. CRD42022380636). A total of nine studies were included, divided into three groups according to the type of study, containing a total of 107 051 and 105 222 women who were supplemented and not supplemented with folic acid during pregnancy. The results showed that folic acid supplementation during pregnancy could not be proven to reduce the risk of preeclampsia.
CONCLUSION
The results of the study suggest that folic acid supplementation alone is not associated with a decreased risk of pre-eclampsia,but the inferences are somewhat limited by the low methodological quality of the included literature, and therefore higher quality studies are needed to prove this point.
Topics: Pre-Eclampsia; Humans; Pregnancy; Folic Acid; Female; Dietary Supplements
PubMed: 38763206
DOI: 10.1016/j.ctim.2024.103052 -
European Journal of Obstetrics,... Jul 2024The use of various methotrexate (MTX) protocols for the treatment of ectopic pregnancy is well established. This study aimed to evaluate the efficacy of single- and... (Comparative Study)
Comparative Study
OBJECTIVE
The use of various methotrexate (MTX) protocols for the treatment of ectopic pregnancy is well established. This study aimed to evaluate the efficacy of single- and double-dose MTX protocols for the treatment of pregnancy of unknown location (PUL).
STUDY DESIGN
This retrospective study was conducted in the Department of Gynaecological Endocrinology, University Hospital, Krakow, Poland. Haemodynamically stable women with PUL were enrolled between January 2014 and September 2023. Demographics, gestational age and treatment outcomes were compared between women in the single-dose MTX group and women in the double-dose MTX group. The primary outcome was the success rate, measured as the number of women treated without surgical intervention. The secondary outcome was the number of days of MTX needed to achieve an appropriate decrease in beta-human chorionic gonadotrophin (β-hCG).
RESULTS
Two hundred and eleven women (mean age 33 ± 1.8 years) with PUL were enrolled in the study, with an overall success rate of 89.1 %. Single- and double-dose MTX protocols were found to have comparable treatment success rates (93 % and 95 %, respectively). Women with lower initial serum β-hCG (<2000 mIU/ml) had higher treatment efficacy compared with women with higher initial serum β-hCG (96.5 % vs 71.4 %), regardless of protocol type. The length of hospital stay for the women treated with the single-dose MTX protocol was 1 day shorter compared with that for the women treated with the double-dose MTX protocol.
CONCLUSION
Single- and double-dose MTX protocols have comparable efficacy and safety, and should be equally considered in women with PUL with initial β-hCG < 2000 mIU/ml.
Topics: Humans; Female; Methotrexate; Pregnancy; Adult; Retrospective Studies; Abortifacient Agents, Nonsteroidal; Pregnancy, Ectopic; Chorionic Gonadotropin, beta Subunit, Human; Treatment Outcome
PubMed: 38762953
DOI: 10.1016/j.ejogrb.2024.05.016