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Arhiv Za Higijenu Rada I Toksikologiju Mar 2024Organophosphorus poisoning is a critical condition that can cause central nervous system depression, respiratory failure, and death early on. As its clinical...
Organophosphorus poisoning is a critical condition that can cause central nervous system depression, respiratory failure, and death early on. As its clinical manifestations closely resemble those of carbamate pesticide poisoning, the aim of this case study is to present a case of misdiagnosis, initially identifying carbofuran poisoning as organophosphate in a patient suspect of a heatstroke. We also present a case of intentional self-poisoning with organophosphate dichlorvos to underline the likelihood of pesticide poisoning in patients exhibiting acute cholinergic symptoms when the ingested substance is not known. In such cases, empirical treatment with atropine and oxime can be started pending timely differential diagnosis to adjust treatment as necessary.
Topics: Humans; Pesticides; Carbamates; Insecticides; Organophosphate Poisoning; Dichlorvos; Poisoning
PubMed: 38548379
DOI: 10.2478/aiht-2024-75-3781 -
Journal of Cancer Research and Clinical... Mar 2024BRAF mutations are found in 1-5% of non-small-cell lung cancer (NSCLC), with V600 and non-V600 accounting for approximately 50% each. It has been confirmed that targeted... (Review)
Review
BRAF mutations are found in 1-5% of non-small-cell lung cancer (NSCLC), with V600 and non-V600 accounting for approximately 50% each. It has been confirmed that targeted therapy with dabrafenib + trametinib is effective in patients with metastatic NSCLC carrying BRAF V600E mutations. Preclinical studies have shown that dabrafenib + trametinib may also have inhibitory effects on some types of non-V600E mutations, especially some class II BRAF mutations. However, the efficacy of dabrafenib + trametinib on non-V600E mutant NSCLC in clinical practice only exists in some case reports. Here, we report a case of NSCLC patient carrying BRAF ex15 p.T599dup, who showed a clinical response to the combined therapy of dabrafenib + trametinib.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Proto-Oncogene Proteins B-raf; Oximes; Mutation; Antineoplastic Combined Chemotherapy Protocols; Mitogen-Activated Protein Kinase Kinases; Imidazoles
PubMed: 38538919
DOI: 10.1007/s00432-024-05675-9 -
ACS Earth & Space Chemistry Mar 2024Agricultural fires are a major source of biomass-burning organic aerosols (BBOAs) with impacts on health, the environment, and climate. In this study, globally relevant...
Agricultural fires are a major source of biomass-burning organic aerosols (BBOAs) with impacts on health, the environment, and climate. In this study, globally relevant BBOA emissions from the combustion of sugar cane in both field and laboratory experiments were analyzed using comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. The derived chemical fingerprints of fresh emissions were evaluated using targeted and nontargeted evaluation approaches. The open-field sugar cane burning experiments revealed the high chemical complexity of combustion emissions, including compounds derived from the pyrolysis of (hemi)cellulose, lignin, and further biomass, such as pyridine and oxime derivatives, methoxyphenols, and methoxybenzenes, as well as triterpenoids. In comparison, laboratory experiments could only partially model the complexity of real combustion events. Our results showed high variability between the conducted field and laboratory experiments, which we, among others, discuss in terms of differences in combustion conditions, fuel composition, and atmospheric processing. We conclude that both field and laboratory studies have their merits and should be applied complementarily. While field studies under real-world conditions are essential to assess the general impact on air quality, climate, and environment, laboratory studies are better suited to investigate specific emissions of different biomass types under controlled conditions.
PubMed: 38533192
DOI: 10.1021/acsearthspacechem.3c00301 -
Advanced Science (Weinheim,... Jun 2024A novel catalytic system for radical cross-coupling reactions based on copper and chiral Pyridyl-bis(imidazole) (PyBim) ligands is described. It overcomes the...
A novel catalytic system for radical cross-coupling reactions based on copper and chiral Pyridyl-bis(imidazole) (PyBim) ligands is described. It overcomes the challenges of chemoselectivity and enantioselectivity, achieving a highly enantioselective vicinal sulfonyl-esterification reaction of alkenes involving sulfur dioxide. This strategy involves the use of earth-abundant metal catalyst, mild reaction conditions, a broad range of substrates (84 examples), high yields (up to 97% yield), and exceptional control over enantioselectivity. The reaction system is compatible with different types of radical precursors, including O-acylhydroxylamines, cycloketone oxime esters, aryldiazonium salts, and drug molecules. Chiral ligand PyBim is identified as particularly effective in achieving the desired high enantioselectivity. Mechanistic studies reveal that copper/PyBim system plays a vital role in C─O coupling, employing an outer-sphere model. In addition, the side arm effect of ligand is observed.
PubMed: 38532287
DOI: 10.1002/advs.202309069 -
Investigational New Drugs Jun 2024Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the...
KEYNOTE-434 part B: A phase 1 study evaluating the combination of epacadostat, pembrolizumab, and chemotherapy in Japanese patients with previously untreated advanced non-small-cell lung cancer.
BACKGROUND
Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC).
METHODS
Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination.
RESULTS
Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%.
CONCLUSION
The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC.
TRIAL REGISTRATION
ClinicalTrials.gov , NCT02862457.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; East Asian People; Japan; Lung Neoplasms; Oximes; Pemetrexed; Sulfonamides
PubMed: 38530565
DOI: 10.1007/s10637-024-01422-6 -
RSC Advances Mar 2024Sch. Bip is an endemic plant commonly employed in the Andes culture to counteract the effects of mountain sickness, and its bioactive molecules could provide new drugs...
Sch. Bip is an endemic plant commonly employed in the Andes culture to counteract the effects of mountain sickness, and its bioactive molecules could provide new drugs for treating hypertension. The purpose was to determine whether the vascular response of the plant bioactive molecules, such as (5-acetyl-6-hydroxy-2-isopropenyl-2,3-dihydrobenzofurane; Sn-I), could be improved by a simple structural modification to synthesize oximes (Ox-Sn-I). We characterized both compounds using IR and NMR spectroscopy and Heteronuclear Multiple Quantum Coherence (HMQC). We investigated vascular relaxation mechanisms in response to Sn-I and Ox-Sn-I using rat aorta and vascular smooth muscle cells (A7r5) as experimental models. Preincubation of aortic rings with Sn-I (10 M) significantly ( < 0.001) decreased the contractile effect in response to phenylephrine (PE) and potassium chloride (KCl). The sensitivity (EC) to PE significantly ( < 0.01) decreased in the presence of Sn-I (10 M), but not with Ox-Sn-I. Sn-I significantly ( < 0.001) reduced the PE-induced contraction under calcium-free conditions. When A7r5 cells were preincubated with Sn-I and Ox-Sn-I (10 M), both compounds blunted the increase in intracellular Ca induced by KCl. 2,3-Dihydrobenzofurane derived from (Sn-I) reduces the contractile response probably by blocking Ca entry through voltage-gated Ca channels (VGCC) in vascular smooth cells. This effect also causes relaxation in rat aorta mediated by reduction of intracellular Ca concentration, rather than an increase of NO generation in endothelial vascular cells.
PubMed: 38528924
DOI: 10.1039/d4ra01058b -
Journal of Psychopharmacology (Oxford,... Jun 2024There is high inter-individual variability in clozapine metabolism due to genetic and non-genetic differences. Patient-specific factors such as smoking, inflammation...
BACKGROUND
There is high inter-individual variability in clozapine metabolism due to genetic and non-genetic differences. Patient-specific factors such as smoking, inflammation indicated by elevated C-reactive protein (CRP), and certain concurrent medications have a significant influence on clozapine metabolism.
AIM
To assess which patient-specific factors best explain variability in clozapine metabolism estimated by clozapine concentration to dose (C/D) ratios.
METHODS
A retrospective cohort analysis using electronic medical data was conducted on 172 inpatients at the BC Psychosis Program. Patients with normal renal and liver function were included if they were on clozapine and had at least one steady-state plasma concentration. The degree of influence of each factor on the variability of clozapine metabolism in the entire cohort and subgroups stratified by fluvoxamine use was evaluated using multiple linear regression analysis of C/D ratios.
RESULTS
Model fit testing showed that the entire cohort model accounts for 52.7% of C/D ratio variability, while the no fluvoxamine and fluvoxamine models accounted for 40.8% and 43.8%. In the entire cohort ( = 172), fluvoxamine use explained the highest variance, and C/D ratios were higher by 30.6% on average. The second strongest predictor was elevated CRP > 10 mg/L, and C/D ratios were higher by 22.9% on average. Subsequently, obesity, nonsmoker status, and female sex explained a significant but modest proportion of variance. Among participants on fluvoxamine ( = 58), only fluvoxamine dose was associated with an increase, and for every 25 mg increase in dose, C/D ratios increased by 5% on average.
CONCLUSION
In a clinical population, this study replicated the relationship between reduced rate of clozapine metabolism and the use of fluvoxamine, elevated CRP, obesity, nonsmoking status, and female sex; and the magnitude of the effects were large enough to be clinically relevant.
Topics: Humans; Clozapine; Female; Male; Adult; Retrospective Studies; Antipsychotic Agents; Psychotic Disorders; Fluvoxamine; Middle Aged; Schizophrenia, Treatment-Resistant; C-Reactive Protein; Dose-Response Relationship, Drug; Cohort Studies; Sex Factors; Young Adult
PubMed: 38520287
DOI: 10.1177/02698811241241394 -
Science Advances Mar 2024The limited capacity of typical materials to resist stress loading, which affects their mechanical performance, is one of the most formidable challenges in materials...
The limited capacity of typical materials to resist stress loading, which affects their mechanical performance, is one of the most formidable challenges in materials science. Here, we propose a bone-inspired stress-gaining concept of converting typically destructive stress into a favorable factor to substantially enhance the mechanical properties of elastomers. The concept was realized by a molecular design of dynamic poly(oxime-urethanes) network with mesophase domains. During external loading, the mesophase domains in the condensed state were aligned into more ordered domains, and the dynamic oxime-urethane bonds served as the dynamic molecular locks disassociating and reorganizing to facilitate and fix the mesophase domains. Consequently, the tensile modulus and strength were enhanced by 1744 and 49.3 times after four cycles of mechanical training, respectively. This study creates a molecular concept with stress-gaining properties induced by repeated mechanical stress loading and will inspire a series of innovative materials for diverse applications.
PubMed: 38517961
DOI: 10.1126/sciadv.adk5177 -
Frontiers in Plant Science 2024is a plant pathogen that causes economic losses in agricultural and forestry industries, including significant destruction to amenity trees within the city of Brisbane...
INTRODUCTION
is a plant pathogen that causes economic losses in agricultural and forestry industries, including significant destruction to amenity trees within the city of Brisbane in Australia. Use of chemical control agents are restricted in public areas, there is therefore an urgent need to investigate biological control approaches. Members of the phylum Actinomycetota, commonly known as actinomycetes, are known for their industrially important secondary metabolites including antifungal agents. They have proven to be ideal candidates to produce environmentally friendly compounds including the volatile organic compounds (VOCs) which can be used as biofumigants.
METHODS
Different species (n=15) previously isolated from the guts of termites and stored in the University of the Sunshine Coast'sMicrobial Library were tested for their antifungal VOCs against .
RESULTS
Fourteen of them were found to display inhibition (39.39-100%) to the mycelial development of the pathogen. Strongest antifungal activity displaying isolates USC-592, USC-595, USC-6910 and USC-6928 against the pathogen were selected for further investigations. Their VOCs were also found to have plant growth promotional activity observed for with an increase of root length (22-36%) and shoot length (26-57%). The chlorophyll content of the test plant had a slight increase of 11.8% as well. Identified VOCs included geosmin, 2-methylisoborneol, 2-methylbutyrate, methylene cyclopentane, β-pinene, dimethyl disulfide, ethyl isovalerate, methoxyphenyl-oxime and α-pinene. Additionally, all 15 Streptomyces isolates were found to produce siderophores and indole acetic acid as well as the enzyme chitinase which is known to break down the fungal cell wall.
DISCUSSION
Findings indicate that termite gut-associated streptomycetes might be used to control by utilizing their wide range of inhibitory mechanisms.
PubMed: 38510434
DOI: 10.3389/fpls.2024.1371285 -
New Biotechnology Jul 2024We report the synthesis of a novel class of metal-complexing peptide-based polymers, which we name HyperMAPs (Hyper-loaded MetAl-complexed Polymers). The controlled...
We report the synthesis of a novel class of metal-complexing peptide-based polymers, which we name HyperMAPs (Hyper-loaded MetAl-complexed Polymers). The controlled solid-phase synthesis of HyperMAPs' scaffold peptide provides our polymer with a well-defined molecular structure that allows for an accurate on-design assembly of a wide variety of metals. The peptide-scaffold features a handle for direct conjugation to antibodies or any other biomolecules by means of a thiol-maleimide-click or aldehyde-oxime reaction, a fluorogenic moiety for biomolecule conjugation tracking, and a well-defined number of functional groups for direct incorporation of metal-chelator complexes. Since metal-chelator complexes are prepared in a separate reaction prior to incorporation to the peptide scaffold, polymers can be designed to contain specific ratios of metal isotopes, providing each polymer with a unique CyTOF spectral fingerprint. We demonstrate the complexing of 21 different metals using two different chelators and provide evidence of the application of HyperMAPs on a 13 parameter CyTOF panel and compare its performance to monoisotopic metal-conjugated antibodies.
Topics: Polymers; Sulfhydryl Compounds; Peptides; Coordination Complexes; Metals; Chelating Agents; Antibodies; Maleimides
PubMed: 38493996
DOI: 10.1016/j.nbt.2024.03.002