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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 -
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 -
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 -
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 -
Expert Review of Anticancer Therapy 2024Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) treatment for ovarian cancer (OC) are ever-changing. This study aimed to compare the efficacy and... (Comparative Study)
Comparative Study Meta-Analysis Review
Comparison of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance therapy for newly-diagnosed and platinum-sensitive recurrent ovarian cancer with mutational status: a systematic review and network meta-analysis.
BACKGROUND
Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) treatment for ovarian cancer (OC) are ever-changing. This study aimed to compare the efficacy and overall safety of available PARPi as maintenance therapy for BRCA mutation status in patients with newly diagnosed and platinum-sensitive recurrent (PSR) OC patients.
RESEARCH DESIGN AND METHODS
Relevant RCTs were systematically retrieved from PubMed and Embase until 31 May 2022. Progression-free survival (PFS) and overall survival (OS) based on mutation status and adverse events (AEs) regardless of mutation were efficacy and safety endpoints.
RESULTS
In newly diagnosed BRCAm-OC patients, olaparib (HR: 0.33; 95% confidence interval [CI]: 0.25, 0.43) and other PARPis [niraparib (HR: 0.40; 95% CI: 0.29, 0.55), rucaparib (HR: 0.40; 95% CI: 0.21, 0.76) and veliparib (HR: 0.44; 95% CI: 0.28, 0.69)] had a statistically significant effect on PFS versus placebo. In BRCAm-PSROC patients, Olaparib exhibited significant benefit (HR: 0.69; 95% CI: 0.54, 0.88) for OS compared to other PARPis. In BRCAwt-PSR OC patients, Olaparib showed a favorable OS benefit than other PARPis (HR: 0.84; 95% CI: 0.57,1.22). Overall, safety profile of all PARPis was acceptable.
CONCLUSION
All PARPis showed significant benefit, with olaparib showing greater benefit in newly diagnosed and PSR OC women.
REGISTRATION
CRD42021288932.
Topics: Female; Humans; Adenosine Diphosphate; Carcinoma, Ovarian Epithelial; Neoplasm Recurrence, Local; Network Meta-Analysis; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Ribose
PubMed: 38174379
DOI: 10.1080/14737140.2023.2298832 -
Journal of Industrial Microbiology &... May 2011This article reviews current co-culture systems for fermenting mixtures of glucose and xylose to ethanol. Thirty-five co-culture systems that ferment either synthetic... (Review)
Review
This article reviews current co-culture systems for fermenting mixtures of glucose and xylose to ethanol. Thirty-five co-culture systems that ferment either synthetic glucose and xylose mixture or various biomass hydrolysates are examined. Strain combinations, fermentation modes and conditions, and fermentation performance for these co-culture systems are compared and discussed. It is noted that the combination of Pichia stipitis with Saccharomyces cerevisiae or its respiratory-deficient mutant is most commonly used. One of the best results for fermentation of glucose and xylose mixture is achieved by using co-culture of immobilized Zymomonas mobilis and free cells of P. stipitis, giving volumetric ethanol production of 1.277 g/l/h and ethanol yield of 0.49-0.50 g/g. The review discloses that, as a strategy for efficient conversion of glucose and xylose, co-culture fermentation for ethanol production from lignocellulosic biomass can increase ethanol yield and production rate, shorten fermentation time, and reduce process costs, and it is a promising technology although immature.
Topics: Coculture Techniques; Ethanol; Fermentation; Glucose; Industrial Microbiology; Microbial Interactions; Pichia; Saccharomyces cerevisiae; Xylose; Zymomonas
PubMed: 21104106
DOI: 10.1007/s10295-010-0894-3 -
Journal of Gastroenterology and... Jan 2019While the prevalence of celiac disease (CD) is increasing globally, the prevalence of tropical sprue (TS) is declining. Still, there are certain regions in the world... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIM
While the prevalence of celiac disease (CD) is increasing globally, the prevalence of tropical sprue (TS) is declining. Still, there are certain regions in the world where both patients with CD and TS exist and differentiation between them is a challenging task. We conducted a systematic review of the literature to find out differentiating clinical, endoscopic, and histological characteristics between CD and TS.
METHODS
Medline, PubMed, and EMBASE databases were searched for keywords: celiac disease, coeliac, celiac, tropical sprue, sprue, clinical presentation, endoscopy, and histology. Studies published between August 1960 and January 2018 were reviewed. Out of 1063 articles available, 12 articles were included in the final analysis.
RESULTS
Between the patients with CD and TS, there was no difference in the prevalence and duration of chronic diarrhea, abdominal distension, weight loss, extent of abnormal fecal fat content, and density of intestinal inflammation. The following features were more common in CD: short stature, vomiting/dyspepsia, endoscopic scalloping/attenuation of duodenal folds, histological high modified Marsh changes, crescendo type of IELosis, surface epithelial denudation, surface mucosal flattening, thickening of subepithelial basement membrane and celiac seropositivity; while those in TS include anemia, abnormal urinary D-xylose test, endoscopic either normal duodenal folds or mild attenuation, histologically decrescendo type of IELosis, low modified Marsh changes, patchy mucosal changes, and mucosal eosinophilia.
CONCLUSIONS
Both patients with CD and TS have overlapping clinical, endoscopic, and histological characteristics, and there is no single diagnostic feature for differentiating CD from TS except for celiac specific serological tests.
Topics: Anemia; Autoantibodies; Body Height; Celiac Disease; Diagnosis, Differential; Dyspepsia; Endoscopy, Gastrointestinal; Humans; Intestinal Mucosa; Sprue, Tropical; Vomiting; Xylose
PubMed: 30069926
DOI: 10.1111/jgh.14403