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European Journal of Nuclear Medicine... Jul 2023Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can...
Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [Lu]Lu-PSMA-617 and [Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.
Topics: Male; Humans; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Nuclear Medicine; Heterocyclic Compounds, 1-Ring; Dipeptides; Lutetium; Treatment Outcome
PubMed: 37246997
DOI: 10.1007/s00259-023-06255-8 -
IUCrData Jun 2023The study of the oxidation of various proteins necessitates scrutiny of the amino acid sequence. Since me-thio-nine (Met) and tyrosine (Tyr) are easily oxidized,...
The study of the oxidation of various proteins necessitates scrutiny of the amino acid sequence. Since me-thio-nine (Met) and tyrosine (Tyr) are easily oxidized, peptides that contain these amino acids are frequently studied using a variety of oxidation methods, including, but not limited to, pulse radiolysis, electrochemical oxidation, and laser flash photolysis. To date, the oxidation of the Met-Tyr dipeptide is not fully understood. Several investigators have proposed a mechanism of intra-molecular electron transfer between the sulfide radical of Met and the Tyr residue. Our elucidation of the structure and absolute configuration of l-Met-l-Tyr monohydrate, CHNOS·HO (systematic name: (2)-2-{[(2)-2-amino-4-methyl-sulfanyl-butano-yl]amino}-3-(4-hy-droxy-phen-yl)propanoic acid monohydrate) is presented herein and provides information about the zwitterionic nature of the dipeptide. We suspect that the zwitterionic state of the dipeptide and its inter-action within the solvent medium may play a major role in the oxidation of the dipeptide. In the crystal, all the potential donor atoms inter-act strong N-H⋯O, C-H⋯O, O-H⋯S, and O-H⋯O hydrogen bonds.
PubMed: 37936870
DOI: 10.1107/S2414314623005515 -
Diabetes Care Sep 2023To study the relationships between artificial sweeteners, accounting for all dietary sources (total and by type of artificial sweetener) and risk of type 2 diabetes...
OBJECTIVE
To study the relationships between artificial sweeteners, accounting for all dietary sources (total and by type of artificial sweetener) and risk of type 2 diabetes (T2D), in a large-scale prospective cohort.
RESEARCH DESIGN AND METHODS
The analyses included 105,588 participants from the web-based NutriNet-Santé study (France, 2009-2022; mean age 42.5 ± 14.6 years, 79.2% women). Repeated 24-h dietary records, including brands and commercial names of industrial products, merged with qualitative and quantitative food additive composition data, enabled artificial sweetener intakes to be accurately assessed from all dietary sources. Associations between artificial sweeteners (total, aspartame, acesulfame potassium [K], and sucralose) and T2D were investigated using Cox proportional hazard models adjusted for potential confounders, including weight variation during follow-up.
RESULTS
During a median follow-up of 9.1 years (946,650 person-years, 972 incident T2D), compared with nonconsumers, higher consumers of artificial sweeteners (i.e., above the sex-specific medians of 16.4 mg/day in men and 18.5 mg/day in women) had higher risks of developing T2D (hazard ratio [HR] 1.69; 95% CI 1.45-1.97; P-trend <0.001). Positive associations were also observed for individual artificial sweeteners: aspartame (HR 1.63 [95% CI 1.38-1.93], P-trend <0.001), acesulfame-K (HR 1.70 [1.42-2.04], P-trend <0.001), and sucralose (HR 1.34 [1.07-1.69], P-trend = 0.013).
CONCLUSIONS
Potential for reverse causality cannot be eliminated; however, many sensitivity analyses were computed to limit this and other potential biases. These findings of positive associations between artificial sweetener intakes and increased T2D risk strengthen the evidence that these additives may not be safe sugar alternatives. This study provides important insights in the context of on-going reevaluation of artificial sweeteners by health authorities worldwide.
Topics: Male; Humans; Female; Adult; Middle Aged; Sweetening Agents; Diabetes Mellitus, Type 2; Aspartame; Prospective Studies; Diet
PubMed: 37490630
DOI: 10.2337/dc23-0206 -
Nutrients Aug 2023Aspartame is the methyl-ester of the aspartate-phenylalanine dipeptide. Over time, it has become a very popular artificial sweetener. However, since its approval by the... (Review)
Review
Aspartame is the methyl-ester of the aspartate-phenylalanine dipeptide. Over time, it has become a very popular artificial sweetener. However, since its approval by the main food safety agencies, several concerns have been raised related to neuropsychiatric effects and neurotoxicity due to its ability to activate glutamate receptors, as well as carcinogenic risks due to the increased production of reactive oxygen species. Within this review, we critically evaluate reports concerning the safety of aspartame. Some studies evidenced subtle mood and behavioral changes upon daily high-dose intake below the admitted limit. Epidemiology studies also evidenced associations between daily aspartame intake and a higher predisposition for malignant diseases, like non-Hodgkin lymphomas and multiple myelomas, particularly in males, but an association by chance still could not be excluded. While the debate over the carcinogenic risk of aspartame is ongoing, it is clear that its use may pose some dangers in peculiar cases, such as patients with seizures or other neurological diseases; it should be totally forbidden for patients with phenylketonuria, and reduced doses or complete avoidance are advisable during pregnancy. It would be also highly desirable for every product containing aspartame to clearly indicate on the label the exact amount of the substance and some risk warnings.
Topics: Male; Female; Pregnancy; Humans; Aspartame; Food Additives; Dipeptides; Affect; Carcinogenesis; Carcinogens; Sweetening Agents
PubMed: 37630817
DOI: 10.3390/nu15163627 -
Nutrients Aug 2023Since its introduction, aspartame-the leading sweetener in U.S. diet sodas (DS)-has been reported to cause neurological problems in some users. In prospective studies,...
Since its introduction, aspartame-the leading sweetener in U.S. diet sodas (DS)-has been reported to cause neurological problems in some users. In prospective studies, the offspring of mothers who consumed diet sodas/beverages (DSB) daily during pregnancy experienced increased health problems. We hypothesized that gestational/early-life exposure to ≥1 DS/day (DS) or equivalent aspartame (ASP: ≥177 mg/day) increases autism risk. The case-control Autism Tooth Fairy Study obtained retrospective dietary recalls for DSB and aspartame consumption during pregnancy/breastfeeding from the mothers of 235 offspring with autism spectrum disorder (ASD: cases) and 121 neurotypically developing offspring (controls). The exposure odds ratios (ORs) for DS and ASP were computed for autism, ASD, and the non-regressive conditions of each. Among males, the DS odds were tripled for autism (OR = 3.1; 95% CI: 1.02, 9.7) and non-regressive autism (OR = 3.5; 95% CI: 1.1, 11.1); the ASP odds were even higher: OR = 3.4 (95% CI: 1.1, 10.4) and 3.7 (95% CI: 1.2, 11.8), respectively ( < 0.05 for each). The ORs for non-regressive ASD in males were almost tripled but were not statistically significant: DS OR = 2.7 (95% CI: 0.9, 8.4); ASP OR = 2.9 (95% CI: 0.9, 8.8). No statistically significant associations were found in females. Our findings contribute to the growing literature raising concerns about potential offspring harm from maternal DSB/aspartame intake in pregnancy.
Topics: Female; Male; Pregnancy; Humans; Aspartame; Autistic Disorder; Case-Control Studies; Autism Spectrum Disorder; Retrospective Studies; Prospective Studies; Diet
PubMed: 37686804
DOI: 10.3390/nu15173772 -
International Journal of Cancer Sep 2023Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with...
Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase-Control (MCC-Spain) study were recruited (2008-2013). The consumption of AS, from table-top sweeteners and artificially sweetened beverages, was assessed through a self-administered and validated food frequency questionnaire (FFQ). Sex-specific quartiles among controls were determined to compare moderate consumers (
Topics: Male; Female; Humans; Sweetening Agents; Aspartame; Spain; Stomach Neoplasms; Diabetes Mellitus
PubMed: 37323037
DOI: 10.1002/ijc.34577 -
Cell Reports Aug 2023C9orf72 repeat expansions are the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly(GR) proteins are toxic to...
C9orf72 repeat expansions are the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly(GR) proteins are toxic to neurons by forming cytoplasmic inclusions that sequester RNA-binding proteins including stress granule (SG) proteins. However, little is known of the factors governing poly(GR) inclusion formation. Here, we show that poly(GR) infiltrates a finely tuned network of protein-RNA interactions underpinning SG formation. It interacts with G3BP1, the key driver of SG assembly and a protein we found is critical for poly(GR) inclusion formation. Moreover, we discovered that N-methyladenosine (m6A)-modified mRNAs and m6A-binding YTHDF proteins not only co-localize with poly(GR) inclusions in brains of c9FTD/ALS mouse models and patients with c9FTD, they promote poly(GR) inclusion formation via the incorporation of RNA into the inclusions. Our findings thus suggest that interrupting interactions between poly(GR) and G3BP1 or YTHDF1 proteins or decreasing poly(GR) altogether represent promising therapeutic strategies to combat c9FTD/ALS pathogenesis.
Topics: Animals; Mice; Humans; Amyotrophic Lateral Sclerosis; DNA Helicases; Stress Granules; DNA Repeat Expansion; Poly-ADP-Ribose Binding Proteins; RNA Helicases; RNA Recognition Motif Proteins; Frontotemporal Dementia; Inclusion Bodies; Heat-Shock Proteins; RNA; C9orf72 Protein
PubMed: 37471224
DOI: 10.1016/j.celrep.2023.112822 -
Nature Communications Jun 2023Secreted proteins are one of the direct molecular mechanisms by which microbiota influence the host, thus constituting a promising field for drug discovery. Here,...
Secreted proteins are one of the direct molecular mechanisms by which microbiota influence the host, thus constituting a promising field for drug discovery. Here, through bioinformatics-guided screening of the secretome of clinically established probiotics from Lactobacillus, we identify an uncharacterized secreted protein (named LPH here) that is shared by most of these probiotic strains (8/10) and demonstrate that it protects female mice from colitis in multiple models. Functional studies show that LPH is a bi-functional peptidoglycan hydrolase with both N-Acetyl-β-D-muramidase and DL-endopeptidase activities that can generate muramyl dipeptide (MDP), a NOD2 ligand. Different active site mutants of LPH in combination with Nod2 knockout female mice confirm that LPH exerts anti-colitis effects through MDP-NOD2 signaling. Furthermore, we validate that LPH can also exert protective effects on inflammation-associated colorectal cancer in female mice. Our study reports a probiotic enzyme that enhances NOD2 signaling in vivo in female mice and describes a molecular mechanism that may contribute to the effects of traditional Lactobacillus probiotics.
Topics: Mice; Female; Animals; Ligands; N-Acetylmuramoyl-L-alanine Amidase; Acetylmuramyl-Alanyl-Isoglutamine; Colitis; Mice, Knockout; Probiotics; Nod2 Signaling Adaptor Protein; Peptidoglycan
PubMed: 37286542
DOI: 10.1038/s41467-023-38950-3 -
Genes & Development Aug 2023Specialized enzymes add methyl groups to the nitrogens of the amino acid histidine, altering the chemical properties of its imidazole ring and, in turn, the function of... (Review)
Review
Specialized enzymes add methyl groups to the nitrogens of the amino acid histidine, altering the chemical properties of its imidazole ring and, in turn, the function of the modified (poly)peptide. In this issue of , Shimazu and colleagues (pp. 724-742) make the remarkable discovery that CARNMT1 acts as a dual-specificity histidine methyltransferase, modifying both the small-molecule dipeptide carnosine and a set of proteins, predominantly within RNA-binding C3H zinc finger (C3H ZF) motifs. As a result, CARNMT1 modulates the activity of its protein targets to affect RNA processing and metabolism, ultimately contributing an essential function during mammalian development.
Topics: Animals; Histidine; Methylation; Amino Acids; Methyltransferases; Organogenesis; Mammals
PubMed: 37673460
DOI: 10.1101/gad.351097.123