Methionine Uptake Research Articles

STMO-11 Supratotal resection of Glioblastoma with Methionine PET

Objective: To assess the resection of both of contrast-enhanced (CE) and methionine-uptake (MU) and the oncological outcome in newly diagnosed glioblastoma. Methods: This retrospective study included a glioblastoma cohort from Chiba University who met the two criteria, i) total resection of CE tumor, ii) preoperative evaluation with methionine positron emission tomography (Met-PET). Data regarding the pattern of recurrence and overall survival were collected. Results: Among 247 cases with glioblastoma, total resection of CE was achieved in 112. Preoperative Met-PET was performed in 30 out of 112. The median age at operation, a period of follow-up, and the preoperative tumor volume in 30 patients were 56 year-old, 17.9 months, and 18.8 cc respectively. The promoter region of the O6-methylguanine-DNA methyltransferase was methylated in 37%. Radiological comparison revealed that Met uptake was detected beyond the CE area in 13 out of 30, and the Met uptake was also resected with awake mapping technique in 7 patients (supratotal resection group; STR). The median progression-free survival (PFS) in STR was 23 months, and all the patterns of recurrence were distant recurrence. In contrast, the PFS in total resection group (TRG) was 9 months (p=0.09, Wilcoxon). Furthermore, 14 out of 17 recurrence were local in TRG subgroup. While the median OS in TRG was 18 months, it has not reached in STR (p=0.04, Wilcoxon). Conclusions: The resection of both of CE and MU was associated with better PFS and OS. This finding must be validated in a larger cohort with a multicenter study.

NI-10 T2/FLAIR mismatch sign and methionine PET uptake in grade II and III gliomas

Background: Recent study suggests that “T2/FLAIR mismatch” sign is specific MRI finding for isocitrate dehydrogenase mutated (IDH-mut) 1p19q non-codeleted gliomas (Grade II and III astrocytic tumors). T2/FLAIR mismatch sign may be useful for predicting the histological type of glioma before surgery. However, it is not known what this finding reflects. Therefore, we examined the correlation between T2/FLAIR mismatch sign and uptake of methionine with positron emission tomography (MET-PET), and molecular classification of glioma.Methods: 74 glioma patients (grade II: 30 cases, grade III: 44 cases) with preoperative MRI and MET-PET who underwent surgical resection during 2000–2019 were included in this study. MR scans were evaluated by 3 independent reviewers to assess presence/absence of T2/FLAIR mismatch sign. The tumor-to-normal (T/N) ratio of methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. We examined the relationship between IDH mutation, 1p/19q codeletion, mismatch, and T/N ratio of MET-PET.Results: Out of the 74 cases, astrocytic tumors (A group: IDH-mutant, 1p19q non-codeleted) were 21 (28%), oligodendroglial tumors (O group: IDH-mutant, 1p19q codeleted) were 19 (26%), and IDH wild tumors (W group) were 34 (46%). The T2/FLAIR mismatch sign was present in 16 cases (22%). The T/N ratio of MET-PET in the tumor with T2/FLAIR mismatch sign was 1.56, which was significantly lower than that in the tumor without mismatch sign (2.01, p=0.016). T2/FLAIR mismatch sign was found in 7 (33%) cases in the A group, 0 (0%) case in the O group and 9 (26%) cases in the W group, and the positive rate was significantly higher in the A group (p=0.013).Conclusions: “T2/FLAIR mismatch” sign was a specific finding for astrocytic tumor, and the cases with positive “T2/FLAIR mismatch” sign had significantly lower MET-PET uptake than that with negative cases.

A Tug-of-War Over Methionine

Nutrient acquisition and metabolism are integral components of cell growth, proliferation, and differentiation programs. In a recent study in Nature, Bian etal. (2020) revealed that cancer cells outcompete Tcells for methionine uptake, resulting in diminished SAM production, attenuated H3K79 dimethylation, decreased STAT5 expression, and impaired Tcell immunity to cancer.

Carbon and sulphur tracing from soil organic sulphur in plants and soil microorganisms

In soils, cysteine and methionine represent the predominant constituents of the low molecular weight organic S, but their role in plant nutrition and soil S cycling is unclear. Cysteine and methionine uptake by pot-cultivated wheat and oilseed rape and their cycling were evaluated using 14C and 35S labelling. About 0.16%–0.30% of 14C from cysteine and methionine was absorbed by the plants after 6 h, indicating that the plants could utilise organic S, with oilseed rape showing higher ability than wheat to take up intact organic S and its derivative inorganic S. Plants utilised organic S with much lower efficiency than inorganic S because most organic S was decomposed by microorganisms. Nitrogen (N) addition enhanced plant S uptake, as high N uptake stimulates S immobilization. About 28%–33% and 67–71% of 14C from cysteine and methionine, respectively, were retained in the microbial biomass (MB), a much higher proportion of 14C from cysteine was released as 14CO2 from the soil than from methionine. Further, 16%–25% and 61%–72% of 35S from cysteine and methionine, respectively, were retained in the MB, and 35%–42% and 5%–9% were released from it as SO42−. Microbial carbon (C) and S use efficiency for cysteine was lower than for methionine, whereas plants utilised higher amounts of cysteine-derived S as sulphate. The higher microbial utilisation rate of methionine by soil microorganisms, compared with cysteine, may reduce the bioavailability of this compound in the soil solution, and, consequently, its uptake by plants.

Methio "mine"! Cancer cells steal methionine and impair CD8 T-cell function.

Tumor cells steal methionine from CD8 T cells. High expression of the methionine transporters SLC7A5 and SLC43A2 allows tumor cells to outcompete CD8 T cells for methionine uptake. Lower methionine concentrations in CD8 T cells lead to reduced levels of dimethylated H3K79, an active epigenetic mark, which in turn results in reduced STAT5 expression and activity.

Soil carbon, nitrogen, and sulphur status affects the metabolism of organic S but not its uptake by microorganisms

Plant sulphur (S) deficiency is a worldwide concern. However, the mechanisms controlling the immobilization and mineralization of low-molecular weight organic S by soil microorganisms remain unclear. Therefore, we investigated the assimilation of carbon (C) and S by soil microorganisms using uniformly 14C- or 35S-labelled cysteine and methionine. The decomposition of cysteine and methionine in the soil occurred in three steps. First, the microbial biomass (MB) rapidly immobilised the added cysteine-S (55%–63%) and methionine-S (81%–84%) in less than 30 min. Subsequently, S in the MB was released as 35S-sulphate (release of S into the soil peaked at 1 h [21.4%] and 24 h [17.3%] after adding cysteine and methionine, respectively). Lastly, the released 35SO42− was reutilised by microorganisms. The amount of 14CO2 and 35SO42− released from methionine was much lower than that from cysteine. The addition of excess glucose-C or inorganic nitrogen and S had little effect on cysteine and methionine uptake rate, but had a major effect on microbial C use efficiency (CUE) and internal S partitioning and the subsequent release of SO42−. We conclude that the microbial community cycles S-containing amino acids at a high rate, irrespective of soil S and N status with a large proportion of the C used in catabolic processes.

A Nomogram Modeling 11C-MET PET/CT and Clinical Features in Glioma Helps Predict IDH Mutation.

Purpose: We developed a 11C-Methionine positron emission tomography/computed tomography (11C-MET PET/CT)-based nomogram model that uses easy-accessible imaging and clinical features to achieve reliable non-invasive isocitrate dehydrogenase (IDH)-mutant prediction with strong clinical translational capability.Methods: One hundred and ten patients with pathologically proven glioma who underwent pretreatment 11C-MET PET/CT were retrospectively reviewed. IDH genotype was determined by IDH1 R132H immunohistochemistry staining. Maximum, mean and peak tumor-to-normal brain tissue (TNRmax, TNRmean, TNRpeak), metabolic tumor volume (MTV), total lesion methionine uptake (TLMU), and standard deviation of SUV (SUVSD) of the lesions on MET PET images were obtained via a dedicated workstation (Siemens. syngo.via). Univariate and multivariate logistic regression models were used to identify the predictive factors for IDH mutation. Nomogram and calibration plots were further performed.Results: In the entire population, TNRmean, TNRmax, TNRpeak, and SUVSD of IDH-mutant glioma patients were significantly lower than these values of IDH wildtype. Receiver operating characteristic (ROC) analysis suggested SUVSD had the best performance for IDH-mutant discrimination (AUC = 0.731, cut-off ≤ 0.29, p < 0.001). All pairs of the 11C-MET PET metrics showed linear associations by Pearson correlation coefficients between 0.228 and 0.986. Multivariate analyses demonstrated that SUVSD (>0.29 vs. ≤ 0.29 OR: 0.053, p = 0.010), dichotomized brain midline structure involvement (no vs. yes OR: 26.52, p = 0.000) and age (≤ 45 vs. >45 years OR: 3.23, p = 0.023), were associated with a higher incidence of IDH mutation. The nomogram modeling showed good discrimination, with a C-statistics of 0.866 (95% CI: 0.796–0.937) and was well-calibrated.Conclusions: 11C-Methionine PET/CT imaging features (SUVSD and the involvement of brain midline structure) can be conveniently used to facilitate the pre-operative prediction of IDH genotype. The nomogram model based on 11C-Methionine PET/CT and clinical age features might be clinically useful in non-invasive IDH mutation status prediction for untreated glioma patients.

The relationship between cholecystokinin secretion and pancreatic [11C]methionine uptake in patients after partial pancreaticoduodenectomy.

The pancreatic uptake of [11C]methionine ([11C]MET) is associated with beta-cell function and insulin secretion, but [11C]MET uptake and its relationship with exocrine pancreatic performance are less well studied. The postprandial release of cholecystokinin (CCK) depends on gastric emptying velocity and triggers exocrine pancreas secretion. Therefore, we assumed that high postprandial CCK concentrations stimulate the uptake of [11C]MET in the residual pancreas following pancreaticoduodenectomy. Nineteen tumor-free patients after pancreaticoduodenectomy (median age: 64; 25/75 quantile: 56-67years); ten males, nine females and ten healthy controls (median age: 24; 25/75 quantile: 23.8-26years) were given a mixed meal. Plasma CCK, insulin and glucose concentrations were measured before and at 10, 20, 30, 60, 90, 150 and 180min after ingestion. Simultaneously, 800MBq of [11C]MET were administered and the activity [maximum tissue standardized uptake values (SUVmax)] over the pancreas was measured using PET-CT at 15, 30 and 60min after injection. Integrated CCK (AUC30) correlated with SUVmax (AUC60, R2 = 0.45, p value = 0.0013). Multivariate analysis revealed postprandial insulin (AUC60) and CCK concentrations and young age as significant independent predictors of [11C] methionine uptake. The association between CCK concentrations and pancreatic [11C]MET uptake might indicate a causal relationship. Further research should assess whether [11C]MET uptake could serve as a less invasive tool to assess exocrine pancreas activity.

A substrate-based ontology for human solute carriers.

Solute carriers (SLCs) are the largest family of transmembrane transporters in the human genome with more than 400 members. Despite the fact that SLCs mediate critical biological functions and several are important pharmacological targets, a large proportion of them is poorly characterized and present no assigned substrate. A major limitation to systems‐level de‐orphanization campaigns is the absence of a structured, language‐controlled chemical annotation. Here we describe a thorough manual annotation of SLCs based on literature. The annotation of substrates, transport mechanism, coupled ions, and subcellular localization for 446 human SLCs confirmed that ~30% of these were still functionally orphan and lacked known substrates. Application of a substrate‐based ontology to transcriptomic datasets identified SLC‐specific responses to external perturbations, while a machine‐learning approach based on the annotation allowed us to identify potential substrates for several orphan SLCs. The annotation is available at https://opendata.cemm.at/gsflab/slcontology/. Given the increasing availability of large biological datasets and the growing interest in transporters, we expect that the effort presented here will be critical to provide novel insights into the functions of SLCs.

Methionine Availability in the Arthropod Intestine Is Elucidated through Identification of Vibrio cholerae Methionine Acquisition Systems.

While only a subset of Vibrio cholerae strains are human diarrheal pathogens, all are aquatic organisms. In this environment, they often persist in close association with arthropods. In the intestinal lumen of the model arthropod Drosophila melanogaster, methionine and methionine sulfoxide decrease susceptibility to V. cholerae infection. In addition to its structural role in proteins, methionine participates in the methionine cycle, which carries out synthetic and regulatory methylation reactions. It is, therefore, essential for the growth of both animals and bacteria. Methionine is scarce in some environments, and the facile conversion of free methionine to methionine sulfoxide in oxidizing environments interferes with its utilization. To ensure an adequate supply of methionine, the genomes of most organisms encode multiple high-affinity uptake pathways for methionine as well as multiple methionine sulfoxide reductases, which reduce free and protein-associated methionine sulfoxide to methionine. To explore the role of methionine uptake and reduction in V. cholerae colonization of the arthropod intestine, we mutagenized the two high-affinity methionine transporters and five methionine sulfoxide reductases encoded in the V. cholerae genome. We show that MsrC is the sole methionine sulfoxide reductase active on free methionine sulfoxide. Furthermore, in the absence of methionine synthesis, high-affinity methionine uptake but not reduction is essential for V. cholerae colonization of the Drosophila intestine. These findings allow us to place a lower limit of 0.05 mM and an upper limit of 0.5 mM on the methionine concentration in the Drosophila intestine.IMPORTANCE Methionine is an essential amino acid involved in both biosynthetic and regulatory processes in the bacterial cell. To ensure an adequate supply of methionine, bacteria have evolved multiple systems to synthesize, import, and recover this amino acid. To explore the importance of methionine synthesis, transport, and recovery in any environment, all of these systems must be identified and mutagenized. Here, we have mutagenized every high-affinity methionine uptake system and methionine sulfoxide reductase encoded in the genome of the diarrheal pathogen V. cholerae We use this information to determine that high-affinity methionine uptake systems are sufficient to acquire methionine in the intestine of the model arthropod Drosophila melanogaster but are not involved in virulence and that the intestinal concentration of methionine must be between 0.05 mM and 0.5 mM.

Characterization of methionine uptake and clearance in the hemolymph of Pacific white shrimp Litopenaeus vannamei

A series of feeding trials were conducted to investigate the absorption rate of amino acids and compare the absorption of different methionine (Met) sources in the hemolymph of Pacific White shrimp, Litopenaeus vannamei. In trial 1, a basal diet was supplemented with three alpha amino acids including DL-Met, lysine and arginine and the beta amino acid taurine. Shrimp were fed with test diets for 30 mins and then the leftover feeds were withdrawn. The hemolymph samples were taken every 30 mins over 5 h after feeding to determine amino acid (AA) concentrations in the hemolymph. Results indicated that total AA, Met and Lys were near their peak after feeding 30 mins and the level declined within 60 mins to near fasting levels. No secondary peaks were observed for any AA. The diet supplemented with AA exhibited higher peaks than the basal diet. The second and third trials focused on the identification of different patterns that would indicate asynchronous absorption and comparison of the absorption of different Met sources. Four experimental diets were produced, including a basal diet (soy protein-based), a DL-Met-supplemented, a dipeptide Met (Met-Met)-supplemented, and a high fishmeal diet (high-Met intact protein) in trial 2. Fasted shrimp were offered diets for 15 mins and then the leftover feeds were removed. The hemolymph samples were taken every 15 mins over a 1 h period after feeding. The results generally confirmed the fast absorption and clearance of AA in shrimp and indicated that the diets containing different Met sources resulted in higher Met levels in the hemolymph as compared to the basal diet. To better define the absorption process and confirm if there may be a synchronous peak during absorption, the third trial simply looked at the uptake of AA over a 1 h period with basal diet and dipeptide Met diet. The shrimp were offered diets for a total of 60 mins during this timeframe intermittent samples were taken at 0, 5, 10, 15, 20, 30, and 60 mins. Results demonstrated the pattern for AA uptake is similar with a clear upswing in AA levels in 10–15 mins after the initiation of feeding. Based on both absorption and clearance patterns of the amino acids, we demonstrated that there were no indications of asynchronous absorption of supplemented amino acids; hence, supplemented amino acids are available for metabolism. In addition, the data also demonstrated higher peak of Met over time in the hemolymph of L. vannamei with the Met-Met supplemented diet versus the DL-Met supplemented diet.

Positron emission tomography with 11C-methionine in primary brain tumor diagnosis

To investigate the variations in 11C-methionine uptake in the intact brain tissue and in glial brain tumors of different types. Forty patients (21 men, 19 women) with gliomas, Grade I-IV, underwent 11C-methionine PET-CT and contrast-enhanced MRI. Standardized uptake value (SUV), tumor-to-normal (T/N) ratios and tumor volume were analyzed. The high inter-subject variability was detected in the intact brain tissue (SUV in the frontal lobe (FL) varies from 0.47 to 1.73). Amino acid metabolism was more active in women than in men (FL SUV 1.32±0.22 and 1.05±0.24, respectively). T/N ratio better differentiates gliomas by the degree of anaplasia compared to SUV. Gliomas of Grade III (T/N=2.64±0.98) were significantly different (p<0.05) from those of Grade IV (T/N=3.83±0.75). The lowest level of methionine uptake was detected in diffuse astrocytomas (T/N=1.52±0.57), which was lower than with anaplastic astrocytomas (T/N=2.34±0.77, p<0.05). 11C-methionine PET-CT was informative in the high/low degree of malignancy differentiation (T/N 1.66±0.71 for Grade I-II and 3.18±1.06 for Grade III-IV, p<0.05). The method was also useful in separating astrocytomas of Grade II and III. The considerable variation of SUV in the intact brain tissue as well as the difference in uptake between selected areas of the brain were revealed.

ML-04 PROGNOSTIC SIGNIFICANCE OF IMMUNOHISTOCHEMICAL SUBTYPES BASED ON THE STAGE OF B-CELL DIFFERENTIATION IN PRIMARY CNS LYMPHOMA

PURPOSEPrimary central nervous system lymphoma (PCNSL) has been immunohistochemically classified into two subtypes, germinal center (GC) B-cell and non-GC B-cell, but prognostic impact of these subtypes remains debated. We investigated clinical features and prognostic significance of newly defined immunohistochemical subtypes that were identified by expression patterns of three B-cell differentiation markers in PCNSL. In addition, we analyzed a factor related to responsiveness to high-dose methotrexate (HD-MTX) chemotherapy.METHODSTumors from 32 PCNSL patients were immunohistochemically evaluated regarding expression of CD10, BCL-6, and MUM-1 and classified into subtypes according to the expression patterns of these markers. Clinical features and prognostic outcome of these subtypes were investigated.RESULTSTwenty-three patients were treated with HD-MTX-based chemotherapy followed by whole-brain radiation therapy (WBRT), and nine were treated with WBRT alone. Three immunohistochemical subtypes were identified, including A-type expressing CD10, BCL-6, and MUM-1 (12 patients), B-type expressing BCL-6 and MUM-1 (12 patients) and C-type expressing MUM-1 only (8 patients). Response rate in the HD-MTX therapy group was 57.1% (4/7) in A-type, 87.5% (7/8) in B-type, and 75% (6/8) in C-type. C-type with the lowest metabolic activity showed significantly longer overall survival than A-type with the higher uptake of methionine (71.6 versus 39.6 months).CONCLUSIONSImmunohistochemical identification of PCNSL based on the B-cell differentiation stage revealed three types of tumors, showing different metabolic activity and survival time. Refined immunohistochemical classification of PCNSL subtypes may become a useful tool for predicting more accurate prognosis and accessing the sensitivity to HD-MTX therapy.

Feasibility study of finalizing the extended adjuvant temozolomide based on methionine positron emission tomography (Met-PET) findings in patients with glioblastoma

In the management of patients with newly diagnosed glioblastoma, there is no standard duration for adjuvant temozolomide treatment. This study aimed to assess the feasibility of finalizing adjuvant temozolomide treatment on the basis of methionine uptake in methionine positron emission tomography (Met-PET). We conducted a retrospective review of glioblastoma patients who underwent more than twelve cycles of temozolomide (extended temozolomide) treatment after resection and concomitant chemoradiotherapy with no evidence of recurrence on MRI. In addition to the methionine uptake value at the completion of extended temozolomide, local and distant recurrence and progression-free survival were also analyzed. Forty-four patients completed the extended temozolomide treatment. Among these, 18 experienced some type of tumor recurrence within one year. A Tmax/Nave value of 2.0 was the optimal cut-off value indicating progression. More than 80% of the patients with low methionine uptake completed the temozolomide treatment, and subsequent basic MRI observations showed no recurrence within one year after Met-PET. Subgroups with high uptake (≥2.0), even with continuation of temozolomide treatment, showed more frequent tumor progression than patients with low uptake (<2.0) who completed the extended temozolomide treatment (p < 0.001, odds ratio 14.7, 95% CI 3.46–62.3). The tumor recurrence rate increased in stepwise manner according to methionine uptake. Finalization of the extended temozolomide treatment on the basis of low uptake value was feasible with a low recurrence rate. Compared to MRI, Met-PET shows better ability to predict tumor progression in long-term glioblastoma survivors with extended temozolomide use.

Postconditioning Accelerates Myocardial Inflammatory Resolution Demonstrated by 14C-Methionine Imaging and Attenuates Ventricular Remodeling After Ischemia and Reperfusion.

Methionine uptake after myocardial infarction has been proven to reflect myocardial inflammation. The effect of postconditioning on the post-infarction inflammatory process, however, remains to be elucidated.Methods and Results:In control (n=22) and postconditioning rats (n=23), the left coronary artery was occluded for 30 min, followed by reperfusion for 1, 3, 7, and 14 days. Postconditioning was performed immediately following the reperfusion. 14C-methinine (0.74 MBq) and 201Tl (14.8 MBq) were injected 20 and 10 min prior to sacrifice, respectively. One minute before sacrifice, 150-180 MBq of 99 mTc-MIBI was injected immediately following the re-occlusion of the left coronary artery to verify the area at risk, and left ventricular triple-tracer autoradiography was performed. To examine the ventricular remodeling, echocardiography was performed 2 months after reperfusion in both groups (n=6 each). In the control rats, the methionine uptake ratios on days 1, 3, 7, and 14 were 0.74±0.12, 1.85±0.16, 1.48±0.10, 1.25±0.04, respectively. With postconditioning, methionine uptake was similar on day 3 (1.90±0.21), but was lower on day 7 (1.23±0.22, P<0.05) and day 14 (1.08±0.09, P<0.005). Echocardiography revealed that postconditioning reduced the ventricular end-diastolic (0.97±0.16 to 0.78±0.12 cm, P<0.05) and systolic (0.85±0.21 to 0.55±0.23 cm, P<0.05) dimensions and improved ventricular percentage fractional shortening (12±6.2 to 29±12 %, P=0.01). 14C-methinine imaging revealed that postconditioning accelerated resolution of inflammation and attenuated ventricular remodeling.

Transcriptional analysis of amino acid, metal ion, vitamin and carbohydrate uptake in butanol-producing Clostridium beijerinckii NRRL B-598.

In-depth knowledge of cell metabolism and nutrient uptake mechanisms can lead to the development of a tool for improving acetone-butanol-ethanol (ABE) fermentation performance and help to overcome bottlenecks in the process, such as the high cost of substrates and low production rates. Over 300 genes potentially encoding transport of amino acids, metal ions, vitamins and carbohydrates were identified in the genome of the butanol-producing strain Clostridium beijerinckii NRRL B-598, based on similarity searches in protein function databases. Transcriptomic data of the genes were obtained during ABE fermentation by RNA-Seq experiments and covered acidogenesis, solventogenesis and sporulation. The physiological roles of the selected 81 actively expressed transport genes were established on the basis of their expression profiles at particular stages of ABE fermentation. This article describes how genes encoding the uptake of glucose, iron, riboflavin, glutamine, methionine and other nutrients take part in growth, production and stress responses of C. beijerinckii NRRL B-598. These data increase our knowledge of transport mechanisms in solventogenic Clostridium and may be used in the selection of individual genes for further research.

DIRECT COMPARISON BETWEEN DIFFUSION-WEIGHTED MRI AND PET/CT WITH [11С]METHIONINE IN PATIENTS WITH CEREBRAL GLIOMAS

The aim of the study was to assess the diagnostic value of MR diffusion imaging (DWI) and hybrid positron emission and computed tomography (PET/CT) with [11C]methionine for glioma grading and to compare the spatial distribution of diffusion restriction and [11C]methionine uptake abnormalities within a tumor.Material and methods: MRI with diffusion sequences and PET/CT with [11C]methionine were performed for 46 patients with untreated histologically proven brain gliomas. Quantitative evaluation included the minimal apparent diffusion coefficient value (ADCmin) in the tumor and maximum [11C]methionine uptake ratio, measured as ratio of highest tumor count density to that of the brain cortex(tumor-to-cortex-T/Cmax). Mean measurements of ADC (ADCmean) and T/C (T/Cmean) were obtained for each tumor. The ADC and T/Cratio values for glioma grading were assessed and correlations were evaluated. In addition PET and ADC images were coregistered to each other.Results: The T/Cmax and ADCmin values were significantly negatively correlated (r=–0,82). The T/Cmean and ADCmean measurements also demonstrated the significant negative correlation (r=0,56). The T/Cmax showed best accuracy in glioma grading. Sites of maximal radiotracer uptake and minimal ADC did not match in 34% of cases and in 66% of tumors the match was partial.Conclusion: Diagnostic accuracy of PET/CT using [11C]methionine in glioma grading exceeds DWI-MRI, and for both methods it is preferable to analyze a small tumor volume. The T/C ratios and ADC measurements demonstrate the significant inverse correlations. High rate of mismatch between spatial distribution of increased [11C]methionine uptake and low ADC areas within a tumor could be a result of different biological features registered by PET and DWI.

ASCT2 Is Involved in SARS-Mediated β-Casein Synthesis of Bovine Mammary Epithelial Cells with Methionine Supply.

The methionine (Met) uptake into mammary cells depends upon the corresponding amino acid (AA) transporters, which play a regulatory role in the mammary protein production beyond transport. Our previous studies have identified that seryl-tRNA synthetase (SARS) could be a novel mediator to regulate essential AA-stimulated casein synthesis in primary bovine mammary epithelial cells (BMECs). However, the regulatory mechanisms of Met in milk protein production in dairy cows remain further clarified. Here, we aimed to investigate the effects of Met on milk protein synthesis in BMECs and explore the underlying mechanism. The effects of Met on the AA transporter, casein synthesis, and the related signaling pathway were evaluated in the BMECs treated with 0.6 mM Met for 6 h combined with or without the inhibition of AA transporter (ASCT2, a neutral AA transporter) activity by the corresponding inhibitor (GPNA). Besides, the effects of SARS on the cells were mainly evaluated in the BMECs treated with 0.6 mM Met for 6 h together with or without SARS knockdown by RNAi interference. The gene expression of AA transporters and pathway-related genes were analyzed by the real-time quantitative polymerase chain reaction method, and the protein expression of related proteins were determined by the western blot assay. Results showed that 0.6 mM Met remarkably enhanced cell growth and β-casein synthesis compared to the supply of other Met concentrations. Among 13 amino acid transporters, 0.6 mM Met highly increased ASCT2 expression. This Met-stimulated ASCT2 expression and the enhanced mammary intracellular Met uptake were both decreased by the addition of 500 μM GPNA, an inhibitor of ASCT2. In the presence of 0.6 mM Met, the inhibition of ASCT2 activity (by GPNA) and SARS expression (by RNAi) both reduced β-casein synthesis. Additionally, 0.6 mM Met increased the gene expression of mTOR, S6K1, 4EBP1, and Akt; in contrast, the inhibition of ASCT2 by GPNA lowered the gene expression of these four genes. Collectively, this work suggests that ASCT2 is involved in the SARS-mediated Met stimulation of β-casein synthesis through enhancing mammary Met uptake and activating the mTOR signaling pathway in BMECs.

Methionine metabolism in health and cancer: a nexus of diet and precision medicine.

Methionine uptake and metabolism is involved in a host of cellular functions including methylation reactions, redox maintenance, polyamine synthesis and coupling to folate metabolism, thus coordinating nucleotide and redox status. Each of these functions has been shown in many contexts to be relevant for cancer pathogenesis. Intriguingly, the levels of methionine obtained from the diet can have a large effect on cellular methionine metabolism. This establishes a link between nutrition and tumour cell metabolism that may allow for tumour-specific metabolic vulnerabilities that can be influenced by diet. Recently, a number of studies have begun to investigate the molecular and cellular mechanisms that underlie the interaction between nutrition, methionine metabolism and effects on health and cancer.

Transport of Methylmercury through the Epithelial Type Amino Acid Transporter System B0

Background: System B0 is a sodium dependent transporter that transports wide variety of neutral amino acids in the intestinal and renal proximal tubular epithelial cells. Methylmercury (MeHg) readily and non-enzymatically reacts with cysteine to form conjugate structurally similar to the amino acid methionine.&#x0D; Objective: In this study, we investigated the molecular mechanism of absorptive transport of MeHg in intestine using Xenopus oocytes expressing hB0AT1 and the uptake of metylmercry-Cys (MeHg-Cys) by heterodimeric amino acids transporter.&#x0D; Methodology: We confirmed the uptake of [14C] L-Leucine a potent substrate for the hB0AT1 amino acids transporter. The uptake of [14C] L-leucine by hB0AT1 was inhibited by MeHg-Cys conjugate, leucine, cysteine, methinine and phenylalanine in concentration–dependent manner. The IC50 of MeHg-Cys conjugate was significantly lower than that of leucine, cysteine, methinine and phenylalanine, indicating that hB0AT1 is a high affinity MeHg transporter. To assess MeHg-Cys conjugate transport, we measured [14C] MeHg uptake in Xenopus oocytes expressing hB0AT1 in presence or absence of sodium. The [14C] MeHg was transport only in the presence of cysteine and the transport was significantly sodium dependent and inhibited by a system B0 inhibitor 2-aminobicyclo-[2,21]- haptane-2-carboxylic acid (BCH).&#x0D; Result: The current findings indicate that hB0AT1 and heterodimeric amino acids absorb MeHg in the form of cysteine conjugate from the intestinal lumen across the brush-border membrane in to the cells and is supposed to be plays a critical role in the pathogenesis of Minamata disease and present results descried a major molecular mechanism by which MeHg is transported across cell membranes and indicate that metal complexes may form a novel class of substrates for amino acid carriers.&#x0D; Conclusion: In this experiment the results also suggest that uptake of Methionine and MeHg-Cys by heterodimeric amino acid transporter is significantly correlated where the uptake of Methionine and MeHg-Cys between heterodimeric amino acid transporter and hB0AT1 is not correlated.&#x0D; Journal of National Institute of Neurosciences Bangladesh, 2019;5(2): 127-136