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1.
Leonurine affected homocysteine-methionine metabolism based on metabolomics and gut microbiota studies of clinical trial samples.
Liao, J, Suguro, R, Zhao, X, Yu, Y, Cui, Y, Zhu, YZ
Clinical and translational medicine. 2021;(10):e535
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The diagnostic performance of 99mTc-methionine single-photon emission tomography in grading glioma preoperatively: a comparison with histopathology and Ki-67 indices.
Rani, N, Singh, B, Kumar, N, Singh, P, Hazari, PP, Jaswal, A, Gupta, SK, Chhabra, R, Radotra, BD, Mishra, AK
Nuclear medicine communications. 2020;(9):848-857
Abstract
OBJECTIVE To characterize glioma preoperatively using quantitative 99mTc-methionine SPECT and comparison with MR-perfusion/spectroscopy and histopatholgical/Ki-67 scoring. METHODS Twenty-nine patients (21M: 8F; mean age 42.3 ± 10.5 years) with clinical and radiological suspicion of glioma assessed by 99mTc-MDM/SPECT and ceMRI. Additionally, 12/29 patients underwent dynamic susceptibility contrast-enhanced (DSCE) MRI and magnetic resonance spectroscopy (MRS) examination. Three patients with benign pathologies were recruited as controls. Histopathological tumor analysis was done in all (n = 29) the patients, and the Ki-67 index was evaluated in 20/29 patients. The target-to-nontarget (T/NT) methionine tumor uptake ratios, normalized cerebral blood volume (nCBV) and metabolites [choline/N-acetyl aspartate (Cho/NAA), Cho/creatine (Cr), Cr/NAA and Cr/Cho) ratios were measured in tumor areas. RESULTS On histopathological analysis, 26/29 patients had glioma (G IV-13; G III-04; G II-09). The mean T/NT ratio in G-II was significantly lower (2.46 ± 2.3) than in G-III (7.13 ± 2.2) and G-IV (5.16 ± 1.2). However, the mean ratio was highest (15.9 ± 6.8) in meningioma (n=3). The T/NT cutoff ratio of 3.08 provided 100% sensitivity, 87.5% specificity for discriminating high-grade glioma (HGG) from low-grade glioma (LGG) disease. Likewise, the nCBV cutoff of 2.43 offered 100% sensitivity and 80% specificity. Only the Cho/NAA cutoff value of greater than 3.34 provided reasonable sensitivity and specificity of 85.7% and 80.0% respectively for this differentiation. T/NT ratio correlated significantly with nCBV and Cho/NAA, Cho/Cr ratios but not with Ki-67. CONCLUSION Quantitative 99mTc-MDM -SPECT provided high sensitivity and specificity to differentiate HGG versus LGG preoperatively and demonstrated a potential role for the differential diagnosis of glial versus nonglial tumors.
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Pilot Phase I Clinical Trial of Methioninase on High-Stage Cancer Patients: Rapid Depletion of Circulating Methionine.
Hoffman, RM, Tan, Y, Li, S, Han, Q, Zavala, J, Zavala, J
Methods in molecular biology (Clifton, N.J.). 2019;:231-242
Abstract
Methionine (MET) has been shown to be a tumor-selective therapeutic target for cancer, since cancer cells require higher amounts of MET to divide and survive than normal cells. This phenomena is known as MET dependence and is probably due to MET overuse by cancer cells. A pilot clinical trial was initially carried out with non-recombinant METase (METase) produced from Pseudomonas putida and subsequently highly purified. No acute clinical toxicity was observed for any criteria measured in the three patients. The depletion of serum MET started within 30 min of the infusion and was maintained for 4 h after the infusion was completed in patient 1 and patient 2. The lowest serum MET levels were 35% and 19% of the pretreatment level, respectively, in patient 1 and patient 2. Patient 3 received a 10 h i.v. infusion of METase without any sign of side effects. MET was depleted over 200-fold from 23.1 to 0.1 μM by the 10-h infusion of patient 3. No clinical toxicity was observed in any criteria measured in patient 3. Subsequently, another pilot Phase I clinical trial was carried out of serum MET depletion in cancer patients by recombinant METase (rMETase) cloned from Pseudomonas putida and produced in E. coli. Patients with advanced breast cancer, lung cancer, renal cancer, and lymphoma were given a single rMETase treatment at doses ranging from 5000 to 20,000 units by i.v. infusion over 6-24 h. No clinical toxicity was observed in any patient after rMETase treatment. rMETase levels were measured at 0.1 to 0.4 units per ml of serum in the patients which correspond to therapeutic levels in vitro. The lowest serum MET levels in rMETase-treated patients were 0.1% of the pretreatment levels corresponding to approximately 0.1 μM, which also correlates to therapeutic levels in vitro as well as in vivo. The results of the METase and rMETase pilot Phase I clinical trials therefore indicate that i.v. infusion of rMETase is safe and effectively depletes its biochemical target of serum MET, suggesting potential efficacy in future clinical trials.
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In-vivo imaging of methionine metabolism in patients with suspected malignant pleural mesothelioma.
Lopci, E, Novellis, P, Testori, A, Rahal, D, Voulaz, E, Bottoni, E, Ferraroli, GM, Crepaldi, A, Ceresoli, GL, Perrino, M, et al
Nuclear medicine communications. 2019;(11):1179-1186
Abstract
OBJECTIVES In-vivo characterization of malignant pleural mesothelioma (MPM) with C-methionine PET/computed tomography (MET PET). METHODS Between September 2014 and February 2016, 30 consecutive patients with clinical suspicion of MPM were prospectively recruited. The study was approved and registered at www.clinicaltrials.gov (NCT02519049). Patients were evaluated at baseline with MET PET (experimental) and fluorine-18 fluorodeoxyglucose PET/computed tomography (FDG PET) (standard). Principal parameters analyzed were SUVmax, SUVmean, metabolic tumor volume (MTV), and metabolic tumor burden (MTB = MTV ×SUVmean). The reference standard for diagnostic performance was based on histology. RESULTS The presence of malignancy was confirmed in 29/30 patients: 23 (76.6%) with MPM (20 epithelioid, two biphasic, and one sarcomatoid), five (16.6%) with adenocarcinoma of the lung, and one (3.3%) with an undifferentiated carcinoma. In one case, diagnosis was benign pleural inflammation. All tumors showed increased uptake of C-methionine: median SUVmax, SUVmean, MTV, and MTB were, respectively, 5.70 [95% confidence interval (CI): 4.51-6.79], 3.15 (95% CI: 2.71-3.40), 33.85 (95% CI: 14.08-66.64), and 105.25 (95% CI: 41.77-215.25). Pathology data revealed MTV and MTB to be significantly higher in nonepithelioid histology (P < 0.05). The other parameters showed a homogeneous distribution across the tumor types. Overall, MET PET identified 49 lymph nodes, compared with 34 nodes on FDG PET, demonstrating a sensitivity of 91% (95% CI: 80-96%), a positive predictive value of 92% (95% CI: 82- 97%), and an accuracy of 85% (P = 0.0042). CONCLUSIONS MET PET is able to characterize MPM lesions regardless of histology. This technique shows higher sensitivity than FDG PET for the identification of secondary lymph nodes.
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Hyperhomocysteinaemia and the risk of recurrent venous thrombosis: results from the MEGA follow-up study.
Hensen, ADO, Lijfering, WM, Cannegieter, SC, Rosendaal, FR, van Hylckama Vlieg, A
British journal of haematology. 2019;(2):219-226
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Abstract
The measurement of homocysteine is still part of routine thrombosis or thrombophilia work-up in many thrombosis centres in the world. Previous observational studies have shown that hyperhomocysteinaemia is associated with an increased risk of first and recurrent venous thrombosis (VT). Randomised trials, however, showed no benefit of homocysteine-lowering therapy on the risk of first or recurrent VT. This discrepancy could be explained by incomplete adjustment for confounders in the observational studies. We investigated in a large population-based follow-up study whether if the levels of homocysteine and its metabolites, methionine and cysteine, were associated with recurrent VT. Approximately three months after discontinuation of anticoagulant treatment, homocysteine, methionine and cysteine concentrations were measured in 2210 patients with VT. During a median follow-up of 6·9 years, 340 patients developed a recurrence (incidence rate, 2·8/100 patient-years). We found that elevated homocysteine concentrations were not associated with an increased risk of recurrent VT, neither as a continuous variable per 5 μmol/l increase (hazard ratio [HR] 0·98 (95% confidence interval [CI], 0·90-1·04)) nor when levels were >95th (>23·0 μmol/l) percentile (HR 1·03 (95% CI, 0·65-1·64)). Similar results were obtained for cysteine and methionine values. We conclude that hyperhomocysteinaemia is not associated with an increased risk of recurrent VT.
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Comparative effects of acute-methionine loading on the plasma sulfur-amino acids in NAC-supplemented HIV+ patients and healthy controls.
Burini, RC, Borges-Santos, MD, Moreto, F, Yu, YM
Amino acids. 2018;(5):569-576
Abstract
In this study, an acute overloading of methionine (MetLo) was used to investigate the trassulfuration pathway response comparing healthy controls and HIV+ patients under their usual diet and dietary N-acetyl-L-cysteine (NAC) supplementation. MetLo (0.1 g Met/kg mass weight) was given after overnight fasting to 20 non-HIV+ control subjects (Co) and 12 HIV+ HAART-treated patients. Blood samples were taken before and after the MetLo in two different 7-day dietary situations, with NAC (1 g/day) or with their usual diet (UD). The amino acids (Met, Hcy, Cys, Tau, Ser, Glu and Gln) and GSH were determined by HPLC and their inflow rate into circulation (plasma) was estimated by the area under the curve (AUC). Under UD, the HIV+ had lower plasma GSH and amino acids (excepting Hcy) and higher oxidative stress (GSSG/GSH ratio), similar remethylation (RM: Me/Hcy + Ser ratio), transmethylation (TM; Hcy/Met ratio) and glutaminogenesis (Glu/Gln ratio), lower transsulfuration (TS: Cys/Hcy + Ser ratio) and Cys/Met ratio and, higher synthetic rates of glutathione (GG: GSH/Cys ratio) and Tau (TG: Tau/Cys ratio). NAC supplementation changed the HIV pattern by increasing RM above control, normalizing plasma Met and TS and, increasing plasma GSH and GG above controls. However, plasma Cys was kept always below controls probably, associatively to its higher consumption in GG (more GSSG than GSH) and TG. The failure of restoring normal Cys by MetLo, in addition to NAC, in HIV+ patients seems to be related to increased flux of Cys into GSH and Tau pathways, probably strengthening the cell-antioxidant capacity against the HIV progression (registered at http://www.clinicaltrials.gov , NCT00910442).
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p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial.
Sperinde, J, Huang, W, Vehtari, A, Chenna, A, Kellokumpu-Lehtinen, PL, Winslow, J, Bono, P, Lie, YS, Petropoulos, CJ, Weidler, J, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018;(13):3046-3052
Abstract
Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial.Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure.Results: In the arm receiving chemotherapy only, increasing log10(p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab (N = 95), increasing log10(p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01).Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3046-52. ©2018 AACR.
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Double-blind placebo-controlled multicenter phase II trial to evaluate D-methionine in preventing/reducing oral mucositis induced by radiation and chemotherapy for head and neck cancer.
Hamstra, DA, Lee, KC, Eisbruch, A, Sunkara, P, Borgonha, S, Phillip, B, Campbell, KCM, Ross, BD, Rehemtulla, A
Head & neck. 2018;(7):1375-1388
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Abstract
BACKGROUND The purpose of this study was to test if oral D-methionine (D-met) reduced mucositis during chemoradiotherapy. METHODS We conducted a placebo-controlled double-blind randomized phase II trial of D-met (100 mg/kg p.o. b.i.d.) testing the rate of severe (grades 3-4) mucositis. RESULTS Sixty patients were randomized. Grade 2 + oral pain was higher with placebo (79% vs 45%; P = .0165), whereas grade 2 + body odor was greater with D-met (3% vs 41%; P = .0015). Mucositis was decreased with D-met by the physician (World Health Organization [WHO], P = .007; Radiation Therapy Oncology Group [RTOG], P = .009) and patient functional scales (RTOG, P = .0023). The primary end point of grades 3 to 4 mucositis on the composite scale demonstrated a decrease with D-met (48% vs 24%; P = .058), which was borderline in significance. A planned secondary analysis of a semiquantitative scoring system noted decreased oral ulceration (2.2 vs 1.5; P = .023) and erythema (1.6 vs 1.1; P = .048) with D-met. CONCLUSION Although not meeting the primary end point, results of multiple assessments suggest that D-met decreased mucositis.
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[11 C]Methionine emerges as a new biomarker for tracking active myeloma lesions.
Lapa, C, Schreder, M, Lückerath, K, Samnick, S, Rudelius, M, Buck, AK, Kortüm, KM, Einsele, H, Rosenwald, A, Knop, S
British journal of haematology. 2018;(5):701-703
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Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women.
Lamers, Y, Coats, B, Ralat, M, Quinlivan, EP, Stacpoole, PW, Gregory, JF
The Journal of nutrition. 2011;(5):835-42
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Abstract
Methionine is the precursor for S-adenosylmethionine (SAM), the major 1-carbon donor involved in >100 transmethylation reactions. Homocysteine produced from SAM must be metabolized either by remethylation for recycling of methionine or transsulfuration to form cystathionine and then cysteine. Pyridoxal 5'-phosphate (PLP) serves as a coenzyme in enzymes involved in transsulfuration as well as for primary acquisition of 1-carbon units used for remethylation and other phases of 1-carbon metabolism. Because the intake of vitamin B-6 is frequently low in humans and metabolic consequences of inadequacy may be amplified in the postprandial state, we aimed to determine the effects of marginal vitamin B-6 deficiency on the postprandial rates of remethylation, transmethylation, overall transsulfuration, and cystathionine synthesis. Healthy, young adults (4 male, 5 female; 20-35 y) received a primed, constant infusion of [1-(13)C]methionine, [methyl-(2)H(3)]methionine, and [5,5,5-(2)H(3)]leucine to quantify in vivo kinetics at normal vitamin B-6 status and after a 28-d dietary vitamin B-6 restriction. Vitamin B-6 restriction lowered the plasma PLP concentration from 49 ± 4 nmol/L (mean ± SEM) to 19 ± 2 nmol/L (P < 0.0001). Mean remethylation, transsulfuration, and transmethylation rates did not change in response to vitamin B-6 restriction; however, the responses to vitamin B-6 restriction varied greatly among individuals. The plasma cystathionine concentration increased from 142 ± 8 to 236 ± 9 nmol/L (P < 0.001), whereas the fractional cystathionine synthesis rate increased by a mean of 12% in 8 of 9 participants. Interrelationships among plasma concentrations of glycine and cystathionine and kinetic results suggest that individual variability occurs in normal postprandial 1-carbon metabolism and in the response to vitamin B-6 restriction.