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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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Methionine oxidation by hydrogen peroxide in peptides and proteins: A theoretical and Raman spectroscopy study.
Sjöberg, B, Foley, S, Cardey, B, Fromm, M, Enescu, M
Journal of photochemistry and photobiology. B, Biology. 2018;:95-99
Abstract
The oxidation of proteins results in their deterioration via the oxidation of reactive amino acids. Oxidation of the amino acid, methionine plays an important role during biological conditions of oxidative stress, and equally a role in protein stability. In this study the oxidation of the methionine residue using the tripeptide GlyMetGly with respect to hydrogen peroxide has been studied using both Raman spectroscopy and DFT calculations. Spectral modifications following the formation of methionine sulfoxide are shown with the appearance of the SO vibration whilst there is also the modification of the CS vibrations at approximately 700 cm-1. The changes in the intensity of the CS stretching band were used to calculate the kinetic rate constant as 7.9 ± 0.6 × 10-3 dm3 mol-1 s-1. The energy barrier for the reaction. is determined both experimentally and using DFT calculations. The reaction of the dairy protein beta-lactoglobulin with hydrogen peroxide is equally studied using the same technique. The solvent accessible surface area of the methionine residues within the protein were also determined and a comparison of the reaction rate constant and the energy barriers of reaction for the oxidation of the tripeptide and for the protein respectively thus, provides information about the role of the protein environment in the oxidation process.
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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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Charge Transfer and π to π* Transitions in the Visible Spectra of Sulfheme Met Isomeric Structures.
Arbelo-López, HD, Rodriguez-Mackenzie, AD, Roman-Morales, EM, Wymore, T, López-Garriga, J
The journal of physical chemistry. B. 2018;(19):4947-4955
Abstract
Since the 1863 discovery of a new green hemoglobin derivative called "sulfhemoglobin", the nature of the characteristic 618 nm absorption band has been the subject of several hypotheses. The experimental spectra are a function of the observation time and interplay between two major sulfheme isomer concentrations (a three- and five-membered ring adduct), with the latter being the dominant isomer at longer times. Thus, time-dependent density functional theory (TDDFT) was used to calculate the sulfheme excited states and visualize the highest occupied molecular orbitals (HOMOs) and lowest unoccupied MOs (LUMOs) of both isomers in order to interpret the transitions between them. These two isomers have distinguishable a1u and a2u HOMO energies. Formation of the three-membered ring SA isomeric structure decreases the energy of the HOMO a1u and a2u orbitals compared to the unmodified heme due to the electron-withdrawing, sulfur-containing, three-membered ring. Conversely, formation of the SC isomeric structure decreases the energy of the HOMO a1u and a2u orbitals due to the electron-withdrawing, sulfur-containing, five-membered ring. The calculations reveal that the absorption spectrum within the 700 nm region arises from a mixture of MOs but can be characterized as π to π* transitions, while the 600 nm region is characterized by π to dπ (d yz, d xz) transitions having components of a deoxy-like derivative.
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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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Prediction of the Hydrogen Peroxide-Induced Methionine Oxidation Propensity in Monoclonal Antibodies.
Agrawal, NJ, Dykstra, A, Yang, J, Yue, H, Nguyen, X, Kolvenbach, C, Angell, N
Journal of pharmaceutical sciences. 2018;(5):1282-1289
Abstract
Methionine oxidation in therapeutic antibodies can impact the product's stability, clinical efficacy, and safety and hence it is desirable to address the methionine oxidation liability during antibody discovery and development phase. Although the current experimental approaches can identify the oxidation-labile methionine residues, their application is limited mostly to the development phase. We demonstrate an in silico method that can be used to predict oxidation-labile residues based solely on the antibody sequence and structure information. Since antibody sequence information is available in the discovery phase, the in silico method can be applied very early on to identify the oxidation-labile methionine residues and subsequently address the oxidation liability. We believe that the in silico method for methionine oxidation liability assessment can aid in antibody discovery and development phase to address the liability in a more rational way.
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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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The interaction between cannabis use and the Val158Met polymorphism of the COMT gene in psychosis: A transdiagnostic meta - analysis.
Vaessen, TSJ, de Jong, L, Schäfer, AT, Damen, T, Uittenboogaard, A, Krolinski, P, Nwosu, CV, Pinckaers, FME, Rotee, ILM, Smeets, APW, et al
PloS one. 2018;(2):e0192658
Abstract
BACKGROUND Neither environmental nor genetic factors are sufficient to predict the transdiagnostic expression of psychosis. Therefore, analysis of gene-environment interactions may be productive. OBJECTIVE A meta-analysis was performed using papers investigating the interaction between cannabis use and catechol-O-methyl transferase (COMT) polymorphism Val158Met (COMTVal158Met). DATA SOURCES PubMed, Embase, PsychInfo. STUDY ELIGIBILITY CRITERIA All observational studies assessing the interaction between COMTVal158Met and cannabis with any psychosis or psychotic symptoms measure as an outcome. STUDY APPRAISAL AND SYNTHESIS METHODS A meta-analysis was performed using the Meta-analysis of Observational Studies in Epidemiology guidelines and forest plots were generated. Thirteen articles met the selection criteria: 7 clinical studies using a case-only design, 3 clinical studies with a dichotomous outcome, and 3 studies analysing a continuous outcome of psychotic symptoms below the threshold of psychotic disorder. The three study types were analysed separately. Validity of the included studies was assessed using "A Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions". RESULTS For case-only studies, a significant interaction was found between cannabis use and COMTVal158Met, with an OR of 1.45 (95% Confidence Interval = 1.05-2.00; Met/Met as the risk genotype). However, there was no evidence for interaction in either the studies including dichotomous outcomes (B = -0.51, 95% Confidence Interval -1.72, 0.70) or the studies including continuous outcomes (B = -0.04 95% Confidence Interval -0.16-0.08). LIMITATION A substantial part of the included studies used the case-only design, which has lower validity and tends to overestimate true effects. CONCLUSION The interaction term between cannabis use and COMTVal158Met was only statistically significant in the case-only studies, but not in studies using other clinical or non-clinical psychosis outcomes. Future additional high quality studies might change current perspectives, yet currently evidence for the interaction remains unconvincing.
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Increased Risk-Taking Behaviour and Brain-Derived Neurotrophic Factor Val66Met Polymorphism Correlates to Decreased Serum Brain-Derived Neurotrophic Factor Level in Heroin Users.
Roviš, D, Černelič Bizjak, M, Vasiljev Marchesi, V, Petelin, A, Jenuš, T, Vidic, S, Drevenšek, G, Jenko Pražnikar, Z
European addiction research. 2018;(4):189-200
Abstract
BACKGROUND This study has examined the relationships and interactions between serum brain-derived neurotrophic factor (BDNF) levels, BDNF Val66Met polymorphism and self-reported risk-taking behaviour in individuals with a history of heroin use undergoing outpatient treatment in comparison to healthy individuals. METHODS We enrolled 167 heroin users and 86 healthy subjects and examined serum BDNF levels, Val66Met polymorphism, and personal characteristics using Connor Davidson Resilience Scale, Risk-taking (RT) propensity questionnaire, and Personality Assessment Inventory. RESULTS Heroin users had significantly higher serum BDNF levels than controls. In addition, serum BDNF levels were significantly higher in Val/Val carriers than in Met/Val or Met/Met in all recruited subjects. Furthermore, a stepwise multiple regression analysis of serum BDNF levels as a dependent variable with related factors showed that in heroin users, Alcohol Use Disorder Identification Test score, anxiety and RT score were found as independent contributors to serum BDNF levels. When performing gene-environment interaction it was additionally found that heroin users with self-reported high risk-taking behaviour had significantly lower levels of serum BDNF among heroin users with the Met allele. CONCLUSIONS These results indicate that genetic variant Met66 decreased the serum BDNF levels in combination with self-reported risk-taking propensity among heroin users. If results of future work confirm the influence of this combined effect between neurotrophic genotype and risk-taking behaviour, 66Met carriers might require higher levels of intervention to overcome their drug use pattern and risky behaviour.
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The use of amino acid PET and conventional MRI for monitoring of brain tumor therapy.
Galldiks, N, Law, I, Pope, WB, Arbizu, J, Langen, KJ
NeuroImage. Clinical. 2017;:386-394
Abstract
Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced MRI. However, the capacity of conventional MRI to differentiate tumor tissue from posttherapeutic effects following neurosurgical resection, chemoradiation, alkylating chemotherapy, radiosurgery, and/or immunotherapy may be limited. Metabolic imaging using PET can provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. This review article focuses predominantly on the amino acid PET tracers 11C-methyl-l-methionine (MET), O-(2-[18F]fluoroethyl)-l-tyrosine (FET) and 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine (FDOPA) and summarizes investigations regarding monitoring of brain tumor therapy.