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European Urology Focus Jun 2024Defining optimal therapeutic sequencing strategies in prostate cancer (PC) is challenging and may be assisted by artificial intelligence (AI)-based tools for an analysis...
BACKGROUND
Defining optimal therapeutic sequencing strategies in prostate cancer (PC) is challenging and may be assisted by artificial intelligence (AI)-based tools for an analysis of the medical literature.
OBJECTIVE
To demonstrate that INSIDE PC can help clinicians query the literature on therapeutic sequencing in PC and to develop previously unestablished practices for evaluating the outputs of AI-based support platforms.
DESIGN, SETTING, AND PARTICIPANTS
INSIDE PC was developed by customizing PubMed Bidirectional Encoder Representations from Transformers. Publications were ranked and aggregated for relevance using data visualization and analytics. Publications returned by INSIDE PC and PubMed were given normalized discounted cumulative gain (nDCG) scores by PC experts reflecting ranking and relevance.
INTERVENTION
INSIDE PC for AI-based semantic literature analysis.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
INSIDE PC was evaluated for relevance and accuracy for three test questions on the efficacy of therapeutic sequencing of systemic therapies in PC.
RESULTS AND LIMITATIONS
In this initial evaluation, INSIDE PC outperformed PubMed for question 1 (novel hormonal therapy [NHT] followed by NHT) for the top five, ten, and 20 publications (nDCG score, +43, +33, and +30 percentage points [pps], respectively). For question 2 (NHT followed by poly [adenosine diphosphate ribose] polymerase inhibitors [PARPi]), INSIDE PC and PubMed performed similarly. For question 3 (NHT or PARPi followed by Lu-prostate-specific membrane antigen-617), INSIDE PC outperformed PubMed for the top five, ten, and 20 publications (+16, +4, and +5 pps, respectively).
CONCLUSIONS
We applied INSIDE PC to develop standards for evaluating the performance of AI-based tools for literature extraction. INSIDE PC performed competitively with PubMed and can assist clinicians with therapeutic sequencing in PC.
PATIENT SUMMARY
The medical literature is often very difficult for doctors and patients to search. In this report, we describe INSIDE PC-an artificial intelligence (AI) system created to help search articles published in medical journals and determine the best order of treatments for advanced prostate cancer in a much better time frame. We found that INSIDE PC works as well as another search tool, PubMed, a widely used resource for searching and retrieving articles published in medical journals. Our work with INSIDE PC shows new ways in which AI can be used to search published articles in medical journals and how these systems might be evaluated to support shared decision-making.
PubMed: 38876943
DOI: 10.1016/j.euf.2024.05.022 -
Journal of Dairy Science Jun 2024The aim of the study was to investigate the impact of potassium-based emulsifying salts (ES; 2% wt/wt concentration) with different phosphate chain lengths [dipotassium...
The aim of the study was to investigate the impact of potassium-based emulsifying salts (ES; 2% wt/wt concentration) with different phosphate chain lengths [dipotassium hydrogenphosphate (KHPO; DKP), tetrapotassium diphosphate (KPO; KTPP), pentapotassium triphosphate (KPO; TKPP)] on the physicochemical, viscoelastic, textural, tribological, thermal, and sensory properties of processed cheese (PC; 40% wt/wt dry matter, 50% wt/wt fat in dry matter) during a 60d storage period (6 ± 2°C). On the whole, the hardness of all PC samples increased with the increasing chain length of ES (DKP < TKPP < KTPP) and the prolonging storage period. Moreover, the hardness results were in accordance with those of the rheological analysis. All PC samples exhibited a more elastic character (G' > G"; tan δ < 1). The type of potassium-based ES affected the binding of water into the structure of the PC. Furthermore, the study confirmed that the manufactured PCs received optimal sensory scores, without any excessive bitterness. It could be concluded that the type of applied ES and storage length affected the functional properties of PC. Finally, the information provided in this study could serve as a tool for the dairy industry to help appropriately select potassium-based ES for PC manufacture with desired properties.
PubMed: 38876214
DOI: 10.3168/jds.2024-24939 -
Cell Metabolism Jun 2024Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed...
Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts from patients with various mitochondrial disorders and cancer cells with electron transport chain (ETC) blockade. These analyses revealed extensive perturbations in purine metabolism, and stable isotope tracing demonstrated that ETC defects suppress de novo purine synthesis while enhancing purine salvage. In human lung cancer, tumors with markers of low oxidative mitochondrial metabolism exhibit enhanced expression of the salvage enzyme hypoxanthine phosphoribosyl transferase 1 (HPRT1) and high levels of the HPRT1 product inosine monophosphate. Mechanistically, ETC blockade activates the pentose phosphate pathway, providing phosphoribosyl diphosphate to drive purine salvage supplied by uptake of extracellular bases. Blocking HPRT1 sensitizes cancer cells to ETC inhibition. These findings demonstrate how cells remodel purine metabolism upon ETC blockade and uncover a new metabolic vulnerability in tumors with low respiration.
PubMed: 38876105
DOI: 10.1016/j.cmet.2024.05.014 -
Respiratory Medicine Case Reports 2024Metastatic pulmonary calcification (MPC) is a metabolic disorder characterized by an ectopic deposition of calcium in the lung parenchyma, prevalent in patients with...
Metastatic pulmonary calcification (MPC) is a metabolic disorder characterized by an ectopic deposition of calcium in the lung parenchyma, prevalent in patients with chronic kidney disease. A combination of parenchymal lung abnormalities on high resolution chest computed tomography (CT) and pulmonary radiotracer uptake in Tc-methyl diphosphate (MDP) bone scintigraphy can establish diagnosis of MPC. We herein present a case of MPC with documented stability of chest CT abnormalities after renal transplant. We also describe novel findings of diffuse pulmonary uptake of F-sodium fluoride, a calcium-avid radiotracer, in positron emission tomography (PET)/CT performed in the same patient.
PubMed: 38872935
DOI: 10.1016/j.rmcr.2024.102043 -
BMC Plant Biology Jun 2024This study examines the impact of titanium dioxide nanoparticles (TiONPs) on gene expression associated with menthol biosynthesis and selected biochemical parameters in...
Studying the impact of titanium dioxide nanoparticles on the expression of pivotal genes related to menthol biosynthesis and certain biochemical parameters in peppermint plants (Mentha Piperita L.).
BACKGROUND
This study examines the impact of titanium dioxide nanoparticles (TiONPs) on gene expression associated with menthol biosynthesis and selected biochemical parameters in peppermint plants (Mentha piperita L.). Menthol, the active ingredient in peppermint, is synthesized through various pathways involving key genes like geranyl diphosphate synthase, menthone reductase, and menthofuran synthase. Seedlings were treated with different concentrations of TiONPs (50, 100, 200, and 300 ppm) via foliar spray. After three weeks of treatment, leaf samples were gathered and kept at -70 °C for analysis.
RESULTS
According to our findings, there was a significant elevation (P ≤ 0.05) in proline content at concentrations of 200 and 300 ppm in comparison with the control. Specifically, the highest proline level was registered at 200 ppm, reaching 259.64 ± 33.33 µg/g FW. Additionally, hydrogen peroxide and malondialdehyde content exhibited a decreasing trend following nanoparticle treatments. Catalase activity was notably affected by varying TiONP concentrations, with a significant decrease observed at 200 and 300 ppm compared to the control (P ≤ 0.05). Conversely, at 100 ppm, catalase activity significantly increased (11.035 ± 1.12 units/mg of protein/min). Guaiacol peroxidase activity decreased across all nanoparticle concentrations. Furthermore, RT-qPCR analysis indicated increased expression of the studied genes at 300 ppm concentration.
CONCLUSIONS
Hence, it can be inferred that at the transcript level, this nanoparticle exhibited efficacy in influencing the biosynthetic pathway of menthol.
Topics: Titanium; Mentha piperita; Menthol; Nanoparticles; Gene Expression Regulation, Plant; Plant Proteins; Plant Leaves; Metal Nanoparticles; Genes, Plant; Hydrogen Peroxide
PubMed: 38862885
DOI: 10.1186/s12870-024-05228-9 -
Nature Communications Jun 2024Focal adhesions form liquid-like assemblies around activated integrin receptors at the plasma membrane. How they achieve their flexible properties is not well...
Focal adhesions form liquid-like assemblies around activated integrin receptors at the plasma membrane. How they achieve their flexible properties is not well understood. Here, we use recombinant focal adhesion proteins to reconstitute the core structural machinery in vitro. We observe liquid-liquid phase separation of the core focal adhesion proteins talin and vinculin for a spectrum of conditions and interaction partners. Intriguingly, we show that binding to PI(4,5)P-containing membranes triggers phase separation of these proteins on the membrane surface, which in turn induces the enrichment of integrin in the clusters. We suggest a mechanism by which 2-dimensional biomolecular condensates assemble on membranes from soluble proteins in the cytoplasm: lipid-binding triggers protein activation and thus, liquid-liquid phase separation of these membrane-bound proteins. This could explain how early focal adhesions maintain a structured and force-resistant organization into the cytoplasm, while still being highly dynamic and able to quickly assemble and disassemble.
Topics: Talin; Focal Adhesions; Cell Membrane; Vinculin; Humans; Animals; Phosphatidylinositol 4,5-Diphosphate; Integrins; Cytoplasm; Protein Binding; Phase Separation
PubMed: 38862544
DOI: 10.1038/s41467-024-49222-z -
Global Medical Genetics Jun 2024Myelodysplastic syndrome (MDS) is a malignant clonal disorder of hematopoietic stem cells which is characterized by morphologic dysplasia. However, the pathological...
Myelodysplastic syndrome (MDS) is a malignant clonal disorder of hematopoietic stem cells which is characterized by morphologic dysplasia. However, the pathological characteristics of megakaryocytes (MKs) in MDS patients with gene mutation are not well established. Bone marrow MK specimens from 104 patients with primary MDS were evaluated, and all patients were distributed into two groups according to gene mutation associated with functional MKs. The morphologic and cellular characteristics of MKs and platelets were recorded and compared. The more frequently mutated genes in MDS patients were (11.54%), (8.65%), (5.77%), and the most common point mutation was p.(R307H) and p.(Q43P). Patients with MK mutation showed a decrease in adenosine diphosphate-induced platelet aggregation, high proportion of CD34 CD61 MKs (10.00 vs. 4.00%, = 0.012), and short overall survival (33.15 vs. 40.50 months, = 0.013). Further, patients with a higher percent of CD34 CD61 MKs (≧20.00%) had lower platelet counts (36.00 × 10 /L vs. 88.50 × 10 /L, = 0.015) and more profound emperipolesis ( = 0.001). By analyzing RNA-sequencing of MKs, differentially expressed mRNA was involved in physiological processes including platelet function and platelet activation, especially for MDS patients with high percent of CD34 CD61 MKs. The high levels of expression of CD62P, CXCL10, and S100A9 mRNA, shown by RNA sequencing, were validated by PCR assay. High proportion of CD34 CD61 MKs was a poor prognostic factor in MDS patients with MK mutation. CD62P, CXCL10, and S100A9 may be the potential targets to evaluate the molecular link between gene defects and platelet function.
PubMed: 38860162
DOI: 10.1055/s-0044-1787752 -
World Journal of Emergency Medicine 2024Chlorfenapyr is used to kill insects that are resistant to organophosphorus insecticides. Chlorfenapyr poisoning has a high mortality rate and is difficult to treat.... (Review)
Review
BACKGROUND
Chlorfenapyr is used to kill insects that are resistant to organophosphorus insecticides. Chlorfenapyr poisoning has a high mortality rate and is difficult to treat. This article aims to review the mechanisms, clinical presentations, and treatment strategies for chlorfenapyr poisoning.
DATA RESOURCES
We conducted a review of the literature using PubMed, Web of Science, and SpringerLink from their beginnings to the end of October 2023. The inclusion criteria were systematic reviews, clinical guidelines, retrospective studies, and case reports on chlorfenapyr poisoning that focused on its mechanisms, clinical presentations, and treatment strategies. The references in the included studies were also examined to identify additional sources.
RESULTS
We included 57 studies in this review. Chlorfenapyr can be degraded into tralopyril, which is more toxic and reduces energy production by inhibiting the conversion of adenosine diphosphate to adenosine triphosphate. High fever and altered mental status are characteristic clinical presentations of chlorfenapyr poisoning. Once it occurs, respiratory failure occurs immediately, ultimately leading to cardiac arrest and death. Chlorfenapyr poisoning is difficult to treat, and there is no specific antidote.
CONCLUSION
Chlorfenapyr is a new pyrrole pesticide. Although it has been identified as a moderately toxic pesticide by the World Health Organization (WHO), the mortality rate of poisoned patients is extremely high. There is no specific antidote for chlorfenapyr poisoning. Therefore, based on the literature review, future efforts to explore rapid and effective detoxification methods, reconstitute intracellular oxidative phosphorylation couplings, identify early biomarkers of chlorfenapyr poisoning, and block the conversion of chlorfenapyr to tralopyril may be helpful for emergency physicians in the diagnosis and treatment of this disease.
PubMed: 38855374
DOI: 10.5847/wjem.j.1920-8642.2024.046 -
Ecotoxicology and Environmental Safety Jul 2024Isoprenoid metabolism and its derivatives took part in photosynthesis, growth regulation, signal transduction, and plant defense to biotic and abiotic stresses. However,...
Isoprenoid metabolism and its derivatives took part in photosynthesis, growth regulation, signal transduction, and plant defense to biotic and abiotic stresses. However, how aluminum (Al) stress affects the isoprenoid metabolism and whether isoprenoid metabolism plays a vital role in the Citrus plants in coping with Al stress remain unclear. In this study, we reported that Al-treatment-induced alternation in the volatilization rate of monoterpenes (α-pinene, β-pinene, limonene, α-terpinene, γ-terpinene and 3-carene) and isoprene were different between Citrus sinensis (Al-tolerant) and C. grandis (Al-sensitive) leaves. The Al-induced decrease of CO assimilation, maximum quantum yield of primary PSII photochemistry (F/F), the lower contents of glucose and starch, and the lowered activities of enzymes involved in the mevalonic acid (MVA) pathway and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway might account for the different volatilization rate of isoprenoids. Furthermore, the altered transcript levels of genes related to isoprenoid precursors and/or derivatives metabolism, such as geranyl diphosphate (GPP) synthase (GPPS) in GPP biosynthesis, geranylgeranyl diphosphate synthase (GGPPS), chlorophyll synthase (CHS) and GGPP reductase (GGPPR) in chlorophyll biosynthesis, limonene synthase (LS) and α-pinene synthase (APS) in limonene and α-pinene synthesis, respectively, might be responsible for the different contents of corresponding products in C. grandis and C. sinensis. Our data suggested that isoprenoid metabolism was involved in Al tolerance response in Citrus, and the alternation of some branches of isoprenoid metabolism could confer different Al-tolerance to Citrus species.
Topics: Aluminum; Terpenes; Citrus; Limonene; Photosynthesis; Bicyclic Monoterpenes; Plant Leaves; Stress, Physiological; Monoterpenes; Hemiterpenes; Cyclohexenes; Sugar Phosphates; Butadienes; Erythritol; Mevalonic Acid; Cyclohexane Monoterpenes; Citrus sinensis; Chlorophyll; Alkyl and Aryl Transferases; Volatilization
PubMed: 38850709
DOI: 10.1016/j.ecoenv.2024.116545 -
BMC Pharmacology & Toxicology Jun 2024Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor...
Antiplatelet therapy is an important factor influencing the postterm patency rate of carotid artery stenting (CAS). Clopidogrel is a platelet aggregation inhibitor mediated by the adenosine diphosphate receptor and is affected by CYP2C19 gene polymorphisms in vivo. When the CYP2C19 gene has a nonfunctional mutation, the activity of the encoded enzyme will be weakened or lost, which directly affects the metabolism of clopidogrel and ultimately weakens its antiplatelet aggregation ability. Therefore, based on network pharmacology, analyzing the influence of CYP2C19 gene polymorphisms on the antiplatelet therapeutic effect of clopidogrel after CAS is highly important for the formulation of individualized clinical drug regimens. The effect of the CYP2C19 gene polymorphism on the antiplatelet aggregation of clopidogrel after CAS was analyzed based on network pharmacology. A total of 100 patients with ischemic cerebrovascular disease who were confirmed by the neurology department and required CAS treatment were studied. CYP2C19 genotyping was performed on all patients via a gene chip. All patients were classified into the wild-type (WT) group (*1/*1), heterozygous mutation (HTM) group (CYP2C19*1/*2, CYP2C19*1/*3), and homozygous mutation (HMM) group (CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3). High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was used to detect the blood concentration of clopidogrel and the plasma clopidogrel clearance (CL) rate in different groups of patients before and after clopidogrel treatment. The platelet aggregation rate of patients with different genotypes was measured by turbidimetry. The incidences of clopidogrel resistance (CR) and stent thrombosis in different groups after three months of treatment were analyzed. The results showed that among the different CYP2C19 genotypes, patients from the HTM group accounted for the most patients, while patients from the HTM group accounted for the least patients. Similarly, the clopidogrel CL of patients in the HMM group was lower than that of patients in the WT group and HTM group (P < 0.01). The platelet inhibition rate of patients in the HMM group was evidently inferior to that of patients in the WT group and HTM group (P < 0.01). The incidence of CR and stent thrombosis in the WT group was notably lower than that in the HTM and HMM groups (P < 0.01). These results indicate that the CYP2C19 gene can affect CR occurrence and stent thrombosis after CAS by influencing clopidogrel metabolism and platelet count.
Topics: Humans; Cytochrome P-450 CYP2C19; Clopidogrel; Platelet Aggregation Inhibitors; Stents; Male; Female; Platelet Aggregation; Aged; Middle Aged; Polymorphism, Genetic; Ticlopidine; Genotype; Carotid Arteries
PubMed: 38845014
DOI: 10.1186/s40360-024-00750-w