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Cancer Medicine Aug 2023Endometrial cancer (EC) is the most common female reproductive system cancer in developed countries with growing incidence and associated mortality, which may be due to...
INTRODUCTION
Endometrial cancer (EC) is the most common female reproductive system cancer in developed countries with growing incidence and associated mortality, which may be due to the growing prevalence of obesity. Metabolism reprogramming including glucose, amino acid, and lipid remodeling is a hallmark of tumors. Glutamine metabolism has been reported to participate in tumor proliferation and development. This study aimed to develop a glutamine metabolism-related prognostic model for EC and explore potential targets for cancer treatment.
METHOD
Transcriptomic data and survival outcome of EC were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed genes related to glutamine metabolism were recognized and utilized to build a prognostic model by univariate and multivariate Cox regressions. The model was confirmed in the training, testing, and the entire cohort. A nomogram combing prognostic model and clinicopathologic features was established and tested. Moreover, we explored the effect of a key metabolic enzyme, PHGDH, on the biological behavior of EC cell lines and xenograft model.
RESULTS
Five glutamine metabolism-related genes, including PHGDH, OTC, ASRGL1, ASNS, and NR1H4, were involved in prognostic model construction. Kaplan-Meier curve suggested that patients recognized as high risk underwent inferior outcomes. The receiver operating characteristic (ROC) curve showed the model was sufficient to predict survival. Enrichment analysis recognized DNA replication and repair dysfunction in high-risk patients whereas immune relevance analysis revealed low immune scores in the high-risk group. Finally, a nomogram integrating the prognostic model and clinical factors was created and verified. Further, knockdown of PHGDH showed cell growth inhibition, increasing apoptosis, and reduced migration. Promisingly, NCT-503, a PHGDH inhibitor, significantly repressed tumor growth in vivo (p = 0.0002).
CONCLUSION
Our work established and validated a glutamine metabolism-related prognostic model that favorably evaluates the prognosis of EC patients. DNA replication and repair may be the crucial point that linked glutamine metabolism, amino acid metabolism, and EC progression. High-risk patients stratified by the model may not be sufficient for immune therapy. PHGDH might be a crucial target that links serine metabolism, glutamine metabolism as well as EC progression.
Topics: Endometrial Neoplasms; Glutamine; Prognosis; Humans; Female; Phosphoglycerate Dehydrogenase; Piperazines; Thioamides; Pyridines; Cell Line, Tumor; Animals; Mice; Mice, Nude; Xenograft Model Antitumor Assays; Molecular Targeted Therapy
PubMed: 37387559
DOI: 10.1002/cam4.6256 -
Journal of Clinical Oncology : Official... Feb 2024Olaparib improved PFS and OS across subgroups of BRCA1/2mut #prostatecancer patients in the PROFOUND phase III trial.
Olaparib improved PFS and OS across subgroups of BRCA1/2mut #prostatecancer patients in the PROFOUND phase III trial.
Topics: Humans; Male; BRCA1 Protein; BRCA2 Protein; Kaplan-Meier Estimate; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant
PubMed: 37963304
DOI: 10.1200/JCO.23.00339 -
The Oncologist Aug 2023Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of... (Review)
Review
Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of effective therapies targeting these mutations has revolutionized the management of advanced GIST. However, following initiation of first-line imatinib, a tyrosine kinase inhibitor (TKI), nearly all patients will develop resistance within 2 years through the emergence of secondary resistance mutations in KIT, typically in the Adenosine Triphosphate (ATP)-binding site or activation loop of the kinase domain. Moreover, some patients have de novo resistance to imatinib, such as those with mutations in PDGFRA exon 18 or those without KIT or PDGFRA mutation. To target resistance, research efforts are primarily focused on developing next-generation inhibitors of KIT and/or PDGFRA, which can inhibit alternate receptor conformations or unique mutations, and compounds that impact complimentary pathogenic processes or epigenetic events. Here, we review the literature on the medical management of high-risk localized and advanced GIST and provide an update on clinical trial approaches to this disease.
Topics: Humans; Imatinib Mesylate; Gastrointestinal Stromal Tumors; Antineoplastic Agents; Piperazines; Pyrimidines; Benzamides; Drug Resistance, Neoplasm; Receptor, Platelet-Derived Growth Factor alpha; Proto-Oncogene Proteins c-kit; Mutation
PubMed: 37315115
DOI: 10.1093/oncolo/oyad167 -
Medicina (Kaunas, Lithuania) Dec 2023Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and... (Review)
Review
Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and vasodilation. By targeting cGMP for degradation, PDE5 inhibits sustained vasodilation. PDE5 operates in diverse anatomical regions, with its upregulation linked to various pathologies, including cancer and neurodegenerative diseases. Sildenafil, a selective PDE5 inhibitor, is prescribed for erectile dysfunction and pulmonary arterial hypertension. However, considering the extensive roles of PDE5, sildenafil might be useful in other pathologies. This review aims to comprehensively explore sildenafil's therapeutic potential across medicine, addressing a gap in the current literature. Recognising sildenafil's broader potential may unveil new treatment avenues, optimising existing approaches and broadening its clinical application.
Topics: Male; Humans; Sildenafil Citrate; Piperazines; Purines; Phosphodiesterase 5 Inhibitors; Cyclic GMP
PubMed: 38138293
DOI: 10.3390/medicina59122190 -
Lancet (London, England) Jan 2024
Topics: Humans; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Piperazines; Pyridines; Mutation; Pyrimidines
PubMed: 38218611
DOI: 10.1016/S0140-6736(23)02035-4 -
Biomaterials Oct 2023Lipid nanoparticles (LNPs) have shown great promise as delivery vehicles to transport messenger ribonucleic acid (mRNA) into cells and act as vaccines for infectious...
Lipid nanoparticles (LNPs) have shown great promise as delivery vehicles to transport messenger ribonucleic acid (mRNA) into cells and act as vaccines for infectious diseases including COVID-19 and influenza. The ionizable lipid incorporated within the LNP is known to be one of the main driving factors for potency and tolerability. Herein, we describe a novel family of ionizable lipids synthesized with a piperazine core derived from the HEPES Good buffer. These ionizable lipids have unique asymmetric tails and two dissimilar degradable moieties incorporated within the structure. Lipids tails of varying lengths, degrees of unsaturation, branching, and the inclusion of additional ester moieties were evaluated for protein expression. We observed several key lipid structure activity relationships that correlated with improved protein production in vivo, including lipid tails of 12 carbons on the ester side and the effect of carbon spacing on the disulfide arm of the lipids. Differences in LNP physical characteristics were observed for lipids containing an extra ester moiety. The LNP structure and lipid bilayer packing, visualized through Cryo-TEM, affected the amount of protein produced in vivo. In non-human primates, the Good HEPES LNPs formulated with an mRNA encoding an influenza hemagglutinin (HA) antigen successfully generated functional HA inhibition (HAI) antibody titers comparable to the industry standards MC3 and SM-102 LNPs, demonstrating their promise as a potential vaccine.
Topics: Animals; Humans; HEPES; Influenza, Human; COVID-19; Influenza Vaccines; Lipid Bilayers; Carbon; Esters; mRNA Vaccines
PubMed: 37480759
DOI: 10.1016/j.biomaterials.2023.122243 -
Vortioxetine - pharmacological properties and use in mood disorders. The current state of knowledge.Psychiatria Polska Dec 2023Vortioxetine is an antidepressant with a unique profile of receptor activity. The pharmacodynamic spectrum of vortioxetine activity is linked to the modulation of not... (Review)
Review
Vortioxetine is an antidepressant with a unique profile of receptor activity. The pharmacodynamic spectrum of vortioxetine activity is linked to the modulation of not only serotoninergic but also noradrenergic and dopaminergic transmission. At the same time, its pharmacokinetic properties determine good tolerance and safety, which are also observed in elderly patients and those burdened with somatic comorbidity. This work aims to sum up the knowledge coming from the most recent studies assessing the efficacy of vortioxetine. The efficacy of vortioxetine in the treatment of depression was confirmed in a large number of open studies, randomized controlled studies with placebo control, and meta-analyses thereof. What is more, the latest research shows that this drug allows depressed patients to achieve not only symptomatic remission but also an improvement of anhedonia and recovery in cognitive and occupational function. Furthermore, there are studies showing that vortioxetine is efficacious in the treatment of elderly patients, as well as subjects who have experienced trauma or suffer from bipolar depression. Vortioxetine is characterized by a good tolerance profile and safety; rarely does it cause severe adverse effects.
Topics: Aged; Humans; Antidepressive Agents; Mood Disorders; Treatment Outcome; Vortioxetine; Randomized Controlled Trials as Topic; Meta-Analysis as Topic
PubMed: 36571300
DOI: 10.12740/PP/OnlineFirst/151570 -
ESC Heart Failure Oct 2023Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF.
METHODS AND RESULTS
The DoPING-HFpEF trial was a phase II single-centre, double-blind, placebo-controlled, randomized cross-over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2-week wash-out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m ); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI -2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6-min walking distance (mean change of -6 [95% CI -18, 7] m vs. -5 [95% CI -22, 22] m, respectively, P = 0.93), N-terminal pro-B-type natriuretic peptide (5 (-156, 166) ng/L vs. -13 (-172, 147) ng/L, P = 0.70), overall quality-of-life (KCCQ and EQ-5D-5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters.
CONCLUSIONS
Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.
Topics: Humans; Male; Female; Aged; Heart Failure; Trimetazidine; Phosphocreatine; Cross-Over Studies; Stroke Volume; Adenosine Triphosphate
PubMed: 37530098
DOI: 10.1002/ehf2.14418 -
Biology Direct Aug 2023Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder...
Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent 'third'-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ~ 5 to 15% of patients. However, it is not fully understood how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adult Drosophila melanogaster consistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.
Topics: Animals; Mice; Aripiprazole; Antipsychotic Agents; Depressive Disorder, Major; Drosophila melanogaster; Electron Transport
PubMed: 37528429
DOI: 10.1186/s13062-023-00375-9 -
Molecules (Basel, Switzerland) Jul 2023A series of novel Mannich bases were designed, synthesized, and screened for their antimicrobial activity. The target compounds were synthesized from...
A series of novel Mannich bases were designed, synthesized, and screened for their antimicrobial activity. The target compounds were synthesized from 4-(3-chlorophenyl)-5-(3-fluorophenyl)-2,4-dihydro-3-1,2,4-triazole-3-thione and different piperazine derivatives. The structures of the products were confirmed by H and C NMR and elemental analysis. The activity of piperazine derivatives against bacteria (Gram-positive: , , , , and ; Gram-negative: , , , and ) and yeasts (, , and ) was determined by the minimum inhibitory concentration and minimum bactericidal concentration values. Significant activity was observed against Gram-positive bacteria, mainly staphylococci (-) and bacteria of the genes of and (), as well as selected strains of Gram-negative bacteria, including bacteria of the family (), while all tested compounds showed high fungistatic activity against spp. yeasts, especially , with MICs ranging from 0.49 µg/mL () to 0.98 µg/mL () and 62.5 µg/mL (). In conclusion, the results obtained confirm the multidirectional antimicrobial activity of the newly synthesized piperazine derivatives. Furthermore, in silico studies suggest that the tested compounds are likely to have good oral bioavailability. The results obtained will provide valuable data for further research into this interesting group of compounds. The library of compounds obtained is still the subject of pharmacological research aimed at finding new interesting biologically active compounds.
Topics: Piperazine; Mannich Bases; Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Gram-Negative Bacteria; Candida; Anti-Infective Agents; Anti-Bacterial Agents
PubMed: 37513434
DOI: 10.3390/molecules28145562