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International Journal of Molecular... May 2023Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by... (Review)
Review
Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.
Topics: Humans; Cardiomyopathies; Metabolic Diseases; Heart Defects, Congenital; Glycosylation; Carbohydrates; Sugars; Chondroitinsulfatases; Pentosyltransferases; Mannosyltransferases; Acetyltransferases
PubMed: 37239976
DOI: 10.3390/ijms24108632 -
Journal of Clinical Oncology : Official... Sep 2022To update the ASCO Biomarkers to Guide Systemic Therapy for Metastatic Breast Cancer (MBC) guideline.
PURPOSE
To update the ASCO Biomarkers to Guide Systemic Therapy for Metastatic Breast Cancer (MBC) guideline.
METHODS
An Expert Panel conducted a systematic review to identify randomized clinical trials and prospective-retrospective studies from January 2015 to January 2022.
RESULTS
The search identified 19 studies informing the evidence base.
RECOMMENDATIONS
Candidates for a regimen with a phosphatidylinositol 3-kinase inhibitor and hormonal therapy should undergo testing for mutations using next-generation sequencing of tumor tissue or circulating tumor DNA (ctDNA) in plasma to determine eligibility for alpelisib plus fulvestrant. If no mutation is found in ctDNA, testing in tumor tissue, if available, should be used. Patients who are candidates for poly (ADP-ribose) polymerase (PARP) inhibitor therapy should undergo testing for germline and pathogenic or likely pathogenic mutations to determine eligibility for a PARP inhibitor. There is insufficient evidence for or against testing for a germline pathogenic variant to determine eligibility for PARP inhibitor therapy in the metastatic setting. Candidates for immune checkpoint inhibitor therapy should undergo testing for expression of programmed cell death ligand-1 in the tumor and immune cells to determine eligibility for treatment with pembrolizumab plus chemotherapy. Candidates for an immune checkpoint inhibitor should also undergo testing for deficient mismatch repair/microsatellite instability-high to determine eligibility for dostarlimab-gxly or pembrolizumab, as well as testing for tumor mutational burden. Clinicians may test for fusions to determine eligibility for TRK inhibitors. There are insufficient data to recommend routine testing of tumors for mutations, for homologous recombination deficiency, or for TROP2 expression to guide MBC therapy selection. There are insufficient data to recommend routine use of ctDNA or circulating tumor cells to monitor response to therapy among patients with MBC.Additional information can be found at www.asco.org/breast-cancer-guidelines.
Topics: Adenosine Diphosphate; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Breast Neoplasms; Circulating Tumor DNA; Class I Phosphatidylinositol 3-Kinases; Female; Fulvestrant; Humans; Immune Checkpoint Inhibitors; Ligands; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerase Inhibitors; Prospective Studies; Retrospective Studies; Ribose
PubMed: 35759724
DOI: 10.1200/JCO.22.01063 -
Journal of Investigative Medicine : the... Aug 2023The therapeutic response heterogeneity in acromegaly persists, despite the medical-surgical advances of recent years. Thus, personalized medicine implementation, which... (Review)
Review
The therapeutic response heterogeneity in acromegaly persists, despite the medical-surgical advances of recent years. Thus, personalized medicine implementation, which focuses on each patient, is justified. Metabolomics would decipher the molecular mechanisms underlying the therapeutic response heterogeneity. Identification of altered metabolic pathways would open new horizons in the therapeutic management of acromegaly. This research aimed to evaluate the metabolomic profile in acromegaly and metabolomics' contributions to understanding disease pathogenesis. A systematic review was carried out by querying four electronic databases and evaluating patients with acromegaly through metabolomic techniques. In all, 21 studies containing 362 patients were eligible. Choline, the ubiquitous metabolite identified in growth hormone (GH)-secreting pituitary adenomas (Pas) by in vivo magnetic resonance spectroscopy (MRS), negatively correlated with somatostatin receptors type 2 expression and positively correlated with magnetic resonance imaging T2 signal and Ki-67 index. Moreover, elevated choline and choline/creatine ratio differentiated between sparsely and densely granulated GH-secreting PAs. MRS detected low hepatic lipid content in active acromegaly, which increased after disease control. The panel of metabolites of acromegaly deciphered by mass spectrometry (MS)-based techniques mainly included amino acids (especially branched-chain amino acids and taurine), glyceric acid, and lipids. The most altered pathways in acromegaly were the metabolism of glucose (particularly the downregulation of the pentose phosphate pathway), linoleic acid, sphingolipids, glycerophospholipids, arginine/proline, and taurine/hypotaurine. Matrix-assisted laser desorption/ionization coupled with MS imaging confirmed the functional nature of GH-secreting PAs and accurately discriminated PAs from healthy pituitary tissue.
Topics: Humans; Acromegaly; Growth Hormone-Secreting Pituitary Adenoma; Magnetic Resonance Imaging; Metabolomics; Adenoma
PubMed: 37139720
DOI: 10.1177/10815589231169452 -
Endocrinology Nov 2023The association between the gut microbiota and thyroid cancer remains controversial. (Meta-Analysis)
Meta-Analysis
CONTEXT
The association between the gut microbiota and thyroid cancer remains controversial.
OBJECTIVE
We aimed to systematically investigate the interactive causal relationships between the abundance and metabolism pathways of gut microbiota and thyroid cancer.
METHODS
We leveraged genome-wide association studies for the abundance of 211 microbiota taxa from the MiBioGen study (N = 18 340), 205 microbiota metabolism pathways from the Dutch Microbiome Project (N = 7738), and thyroid cancer from the Global Biobank Meta-analysis Initiative (N cases = 6699 and N participants = 1 620 354). We performed a bidirectional Mendelian randomization (MR) to investigate the causality from microbiota taxa and metabolism pathways to thyroid cancer and vice versa. We performed a systematic review of previous observational studies and compared MR results with observational findings.
RESULTS
Eight taxa and 12 metabolism pathways had causal effects on thyroid cancer, where RuminococcaceaeUCG004 genus (P = .001), Streptococcaceae family (P = .016), Olsenella genus (P = .029), ketogluconate metabolism pathway (P = .003), pentose phosphate pathway (P = .016), and L-arginine degradation II in the AST pathway (P = .0007) were supported by sensitivity analyses. Conversely, thyroid cancer had causal effects on 3 taxa and 2 metabolism pathways, where the Holdemanella genus (P = .015) was supported by sensitivity analyses. The Proteobacteria phylum, Streptococcaceae family, Ruminococcus2 genus, and Holdemanella genus were significantly associated with thyroid cancer in both the systematic review and MR, whereas the other 121 significant taxa in observational results were not supported by MR.
DISCUSSIONS
These findings implicated the potential role of host-microbiota crosstalk in thyroid cancer, while the discrepancy among observational studies calls for further investigations.
Topics: Humans; Gastrointestinal Microbiome; Genome-Wide Association Study; Microbiota; Thyroid Neoplasms
PubMed: 38051644
DOI: 10.1210/endocr/bqad184 -
Medicina (Kaunas, Lithuania) Dec 2023: Several recent randomized controlled trials (RCTs) have reported on the survival benefits of poly (ADP-ribose) polymerase inhibitors (PARPi) compared to... (Meta-Analysis)
Meta-Analysis Review
: Several recent randomized controlled trials (RCTs) have reported on the survival benefits of poly (ADP-ribose) polymerase inhibitors (PARPi) compared to standard-of-care (SOC) treatment (enzalutamide, abiraterone, or docetaxel) in patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is a limited integrated analysis of high-quality evidence comparing the efficacy and safety of PARPi and SOC treatments in this context. : This study aims to comprehensively analyze the survival benefits and adverse events associated with PARPi and SOC treatments through a head-to-head meta-analysis in mCRPC. : A systematic review search was conducted in PubMed, Embase, Clinical trials, and the Central Cochrane Registry in July 2023. RCTs were assessed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The systematic review was prospectively registered on PROSPERO (CRD42023441034). : A total of 8 studies, encompassing 2341 cases in the PARPi treatment arm and 1810 cases in the controlled arm, were included in the qualitative synthesis. The hazard ratio (HR) for radiographic progression-free survival (rPFS) and overall survival (OS) were 0.74 (95% CI, 0.61-0.90) and 0.89 (95% CI, 0.80-0.99), respectively, in the intention-to-treatment patients. For subgroup analysis, HRs for rPFS and OS in the BRCA-mutated subgroup were 0.39 (95% CI, 0.28-0.55) and 0.62 (95% CI, 0.38-0.99), while in the HRR-mutated subgroup, HR for rPFS was 0.57 (95% CI, 0.48-0.69) and for OS was 0.77 (95% CI, 0.64-0.93). The odds ratio (OR) for all grades of adverse events (AEs) and AEs with severity of at least grade 3 were 3.86 (95% CI, 2.53-5.90) and 2.30 (95% CI, 1.63-3.26), respectively. : PARP inhibitors demonstrate greater effectiveness than SOC treatments in HRR/BRCA-positive patients with mCRPC. Further research is required to explore ways to reduce adverse event rates and investigate the efficacy of HRR/BRCA-negative patients.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Ribose; Disease-Free Survival; Randomized Controlled Trials as Topic
PubMed: 38138301
DOI: 10.3390/medicina59122198 -
Acta Paediatrica (Oslo, Norway : 1992) Aug 2021To systematically review human metabolomic studies investigating metabolic responses in septic neonates. (Review)
Review
AIM
To systematically review human metabolomic studies investigating metabolic responses in septic neonates.
METHODS
A systematic literature search was performed in the databases MEDLINE, EMBASE and Cochrane library up to the 1st of January 2021. We included studies that assessed neonatal sepsis and the following outcomes; (1) change in the metabolism compared to healthy neonates and/or (2) metabolomics compared to traditional diagnostic tools of neonatal sepsis. The screened abstracts were independently considered for eligibility by two researchers.
PROSPERO ID
CRD42020164454.
RESULTS
The search identified in total 762 articles. Fifteen articles were assessed for eligibility. Four studies were included, with totally 78 neonates. The studies used different diagnostic criteria and had between 1 and 16 sepsis cases. All studies with bacterial sepsis found alterations in the glucose and lactate metabolism, reflecting possible redistribution of glucose consumption from mitochondrial oxidative phosphorylation to the lactate and pentose phosphate pathway. We also found signs of increased oxidative stress and fatty acid oxidation in sepsis cases.
CONCLUSION
We found signs of metabolomic signatures in neonatal sepsis. This may lead to better understanding of sepsis pathophysiology and detection of new candidate biomarkers. Results should be validated in large-scale multicentre studies.
Topics: Anti-Bacterial Agents; Humans; Infant, Newborn; Metabolomics; Neonatal Sepsis; Research Design; Sepsis
PubMed: 33851423
DOI: 10.1111/apa.15874 -
Journal of Cachexia, Sarcopenia and... Jun 2024Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for...
BACKGROUND
Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.
METHODS
We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-C]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.
RESULTS
The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-C]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8).
CONCLUSIONS
Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.
Topics: Glucose; Muscle, Skeletal; Animals; Mice; Humans; Hypertrophy; Muscle Fibers, Skeletal; Insulin-Like Growth Factor I; Metabolomics
PubMed: 38742477
DOI: 10.1002/jcsm.13468 -
BJU International Dec 2023To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic... (Meta-Analysis)
Meta-Analysis Review
Poly(adenosine diphosphate-ribose) polymerase inhibitor combinations in first-line metastatic castrate-resistant prostate cancer setting: a systematic review and meta-analysis.
OBJECTIVES
To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving a combination of first-line poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) plus androgen receptor axis-targeted agents (ARAT) vs placebo/ARAT.
MATERIALS AND METHODS
We conducted a systematic review/meta-analysis of all published Phase III randomised controlled trials using EMBASE, MEDLINE, and Cochrane (inception until 6 June 2023). Published full-text manuscripts and conference abstracts were inclusion eligible. Study selection/data extraction were independently performed by two authors. The Cochrane Risk-of-Bias 2 Tool was used, and certainty of evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Pooled hazard ratios (HRs) and relative risks, with corresponding confidence intervals (CIs), were generated using random-effects models.
RESULTS
Three trials were identified: PROpel, MAGNITUDE, and TALAPRO-2. Compared to placebo/ARAT, the PARPi/ARAT combination was associated with a 35% rPFS improvement in the overall cohort (HR 0.65, 95% CI 0.56-0.76), with 68%, 45%, and 26% improvements in the BReast CAncer gene 1/gene 2 (BRCA1/2)-mutated (BRCA1/2m; P < 0.001), homologous recombination repair-mutated (HRRm; P < 0.001), and non-HRRm cohorts (P = 0.003), respectively. OS data maturity ranged from 31% to 48%, with overall cohort OS data unavailable from MAGNITUDE. The PROpel/TALAPRO-2 pooled analysis demonstrated a 16% OS improvement in the overall cohort (HR 0.84, 95 CI 0.72-0.98; P = 0.02). OS in the HRRm (HR 0.76, 95% CI 0.61-0.95) and the BRCA1/2m cohorts (HR 0.53, 95% CI 0.18-1.56) were improved, with a higher effect magnitude compared to the overall cohort. This combination was associated with a 45% relative risk increase in Grade ≥3 TEAEs, including 6.22-fold for Grade ≥3 anaemia (31.9% vs 4.9%).
CONCLUSIONS
The addition of PARPi to ARAT in the first-line mCRPC setting is associated with rPFS benefits across subgroups, with the greatest magnitude of benefit in BRCA1/2m patients. OS benefits remain inconsistent irrespective of HRRm status, with significant increases in Grade ≥3 TEAEs, particularly anaemia. Currently, we suggest this combined approach be selectively offered to HRRm patients, preferentially BRCA1/2m.
Topics: Male; Humans; BRCA1 Protein; Ribose; Prostatic Neoplasms, Castration-Resistant; BRCA2 Protein; Anemia; Adenosine Diphosphate
PubMed: 37461140
DOI: 10.1111/bju.16130 -
Experimental Dermatology May 2022The skin's ability to function optimally is affected by many diverse factors. Metabolomics has a great potential to improve our understanding of the underlying metabolic... (Review)
Review
The skin's ability to function optimally is affected by many diverse factors. Metabolomics has a great potential to improve our understanding of the underlying metabolic changes and the affected pathways. Therefore, the objective of this study was to review the current state of the literature and to perform further metabolic pathway analysis on the obtained data. The aim was to gain an overview of the metabolic changes under altered conditions and to identify common and different patterns as a function of the investigated factors. A cross-study comparison of the extracted studies from different databases identified 364 metabolites, whose concentrations were considerably altered by the following factor groups: irradiation, xenobiotics, ageing and skin diseases (mainly psoriasis). Using metabolic databases and pathway analysis tools, the individual metabolites were assigned to the corresponding metabolic pathways and the most strongly affected signalling pathways were identified. All factors induced oxidative stress. Thus, antioxidant defence systems, especially coenzyme Q (ageing) and the glutathione system (irradiation, ageing, xenobiotics), were impacted. Lipid metabolism was also impacted by all factors studied. The carnitine shuttle as part of β-oxidation was activated by all factor groups except ageing. Glycolysis, Krebs (TCA) cycle and purine metabolism were mainly affected by irradiation and xenobiotics. The pentose phosphate pathway was activated, and Krebs cycle was downregulated in response to oxidative stress. In summary, it can be ascertained that mainly energy metabolism, lipid metabolism, antioxidative defence and DNA repair systems were impacted by the factors studied.
Topics: Citric Acid Cycle; Energy Metabolism; Metabolomics; Pentose Phosphate Pathway; Xenobiotics
PubMed: 35030266
DOI: 10.1111/exd.14529 -
Current Oncology (Toronto, Ont.) Dec 2023Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for... (Review)
Review
Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, ClinicalTrials.gov and ASCO-GU annual meeting abstracts up to March 2023 to identify potential phase III trials reporting the use of combining PARP inhibitors with NHT in the first-line setting for mCRPC. A total of four phase III trials met the criteria for subsequent review. Emerging data suggested that the radiographic progression-free survival (rPFS) was significantly longer in the PARP inhibitor combined with NHT group versus the placebo plus NHT group for the first-line setting of biomarker-unselected mCRPC patients, especially for patients with homologous recombination repair (HRR) mutation (HRR m), and with the greatest benefit for BRCA1/2 mutation (BRCA1/2 m) populations. Final overall survival (OS) data of the PROpel trial indicated a significant improvement in median OS for mCRPC patients with HRR m and BRCA1/2 m receiving olaparib + abiraterone. Prior taxane-based chemotherapy might not influence the efficacy of the combination. Compared with the current standard-of-care therapies, combining NHT with PARP inhibitors could achieve a significant survival benefit in the first-line setting for mCRPC patients with HRR and BRCA1/2 mutations.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; BRCA1 Protein; Ribose; BRCA2 Protein; Antineoplastic Agents
PubMed: 38132385
DOI: 10.3390/curroncol30120751