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Stroke Aug 2022To emphasize treatment speed for time-sensitive conditions, emergency medicine has developed not only the concept of the golden hour, but also the platinum half-hour....
BACKGROUND
To emphasize treatment speed for time-sensitive conditions, emergency medicine has developed not only the concept of the golden hour, but also the platinum half-hour. Patients with acute stroke treated within the first half-hour of onset have not been previously characterized.
METHODS
In this cohort study, we analyzed patients enrolled in the FAST-MAG (Field Administration of Stroke Therapy-Magnesium) trial, testing paramedic prehospital start of neuroprotective agent ≤2 hours of onset. The features of all acute cerebral ischemia, and intracranial hemorrhage patients with treatment starting at ≤30 m of last known well were compared with later-treated patients.
RESULTS
Among 1680 patients, 203 (12.1%) received study agents within 30 minutes of last known well. Among platinum half-hour patients, median onset-to-treatment time was 28 minutes (interquartile range, 25-30), and final diagnoses were acute cerebral ischemia in 71.8% (ischemic stroke, 61.5%, TIA 10.3%); intracranial hemorrhage in 26.1%; and mimic in 2.5%. Clinical features among platinum half-hour patients were largely similar to later-treated patients and included age 69 (interquartile range, 57-79), 44.8% women, prehospital Los Angeles Motor Scale median 4 (3-5), and early-postarrival National Institutes of Health Stroke Scale deficit 8 (interquartile range, 3-18). Platinum half-hour acute cerebral ischemia patients did have more severe prehospital motor deficits and younger age; platinum half-hour intracranial hemorrhage patients had more severe motor deficits, were more often female, and less often of Hispanic ethnicity. Outcomes at 3 m in platinum half-hour patients were comparable to later-treated patients and included freedom-from-disability (modified Rankin Scale score, 0-1) in 35.5%, functional independence (modified Rankin Scale score, 0-2) in 53.2%, and mortality in 17.7%.
CONCLUSIONS
Prehospital initiation permits treatment start within the platinum half-hour after last known well in a substantial proportion of acute ischemic and hemorrhagic stroke patients, accounting for more than 1 in 10 enrolled in a multicenter trial. Hyperacute platinum half-hour patients were largely similar to later-treated patients and are an attainable target for treatment in prehospital stroke trials.
Topics: Acute Disease; Aged; Brain Ischemia; Cohort Studies; Female; Humans; Intracranial Hemorrhages; Male; Platinum; Stroke; Thrombectomy; Treatment Outcome
PubMed: 35545939
DOI: 10.1161/STROKEAHA.121.036993 -
Nanoscale Sep 2023Catalytic conversion of glucose represents an interesting field of research with multiple applications. From the biotechnology point of view, glucose conversion leads to...
Catalytic conversion of glucose represents an interesting field of research with multiple applications. From the biotechnology point of view, glucose conversion leads to the fabrication of different added-value by-products. In the field of nanocatalytic medicine, the reduction of glucose levels within the tumor microenvironment (TME) represents an appealing approach based on the starvation of cancer cells. Glucose typically achieves high conversion rates with the aid of glucose oxidase (GOx) enzymes or by fermentation. GOx is subjected to degradation, possesses poor recyclability and operates under very specific reaction conditions. Gold-based materials have been typically explored as inorganic catalytic alternatives to GOx in order to convert glucose into building block chemicals of interest. Still, the lack of sufficient selectivity towards certain products such as gluconolactone, the requirement of high fluxes of oxygen or the critical size dependency hinder their full potential, especially in liquid phase reactions. The present work describes the synthesis of platinum-based nanodendrites as novel enzyme-mimicking inorganic surrogates able to convert glucose into gluconolactone with outstanding selectivity values above 85%. We have also studied the enzymatic behavior of these Pt-based nanozymes using the Michaelis-Menten and Lineweaver-Burk models and used the main calculation approaches available in the literature to determine highly competitive glucose turnover rates for Pt or Pt-Au nanodendrites.
Topics: Glucose Oxidase; Catalysis; Gluconates; Glucose; Platinum
PubMed: 37609926
DOI: 10.1039/d3nr02026f -
Scientific Reports Jul 2017Platinum-based chemotherapy is a major therapeutic regimen of lung cancer. Various single nucleotide polymorphisms (SNPs) reported were associated with platinum-based...
Platinum-based chemotherapy is a major therapeutic regimen of lung cancer. Various single nucleotide polymorphisms (SNPs) reported were associated with platinum-based chemotherapy response and drug toxicity. However, neither of the studies explored this association from SNP-SNP interaction perspective nor taking into effects of SNP-environment consideration simultaneously. We genotyped 504 polymorphisms and explore the association of gene-gene and gene-environment interactions with platinum-based chemotherapy response and toxicity in 490 NSCLC patients. 16 SNPs were found significantly associated with platinum-based chemotherapy, and they were picked out as study object in the validation cohort. We recruited 788 patients in the validation cohort. We found that HSPD1 rs17730989-SUMF1 rs2633851 interaction was associated with platinum-based chemotherapy-induced hematologic toxicity (adjusted OR = 0.233, P = 0.018). In addition, the combined effect of ABCG2 rs2231142-CES5A rs3859104 was significantly associated with overall toxicity (adjusted OR = 8.044, P = 4.350 × 10). Besides, the model of ARHGAP26 rs3776332-ERCC6 rs2228528-SLC2A1 rs4658-histology was associated with platinum-based chemotherapeutic response. Gene-gene and gene-environment interactions have been identified to contribute to chemotherapy sensitivity and toxicity. They can potentially predict drug response and toxicity of platinum-based chemotherapy in NSCLC patients.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Doxorubicin; Epistasis, Genetic; Female; Gene-Environment Interaction; Humans; Lung Neoplasms; Male; Middle Aged; Platinum; Reproducibility of Results
PubMed: 28698656
DOI: 10.1038/s41598-017-05246-8 -
International Journal of Gynecological... Nov 2023Immune checkpoint inhibitors have emerged as novel treatment options in patients with endometrial cancer. In this study we aimed to compare the survival outcomes of...
Outcomes of dostarlimab versus chemotherapy in post-platinum patients with recurrent/advanced endometrial cancer: data from the GARNET trial and the National Cancer Registration Service in England.
OBJECTIVES
Immune checkpoint inhibitors have emerged as novel treatment options in patients with endometrial cancer. In this study we aimed to compare the survival outcomes of patients with recurrent or advanced endometrial cancer. These patients had received dostarlimab after platinum-based chemotherapy in the single-arm, Phase I GARNET trial. We compared them with a matched indirect real-world cohort.
METHODS
The real-world cohort was established using National Cancer Registration and Analysis Service data, with five treatment-specific real-world sub-cohorts identified. To compare clinical outcomes between the GARNET trial and real-world cohorts, we performed matching-adjusted indirect comparisons. We used prognostic variables to create matching scenarios, including scenario 1 that incorporated grade, histology, and platinum-based chemotherapy number; scenario 2 that considered histology and platinum-based chemotherapy number; and scenario 3 that included race/ethnicity, stage at diagnosis, histology, and prior surgery. Overall survival was defined as the time between the first dostarlimab dose or second-line real-world treatment and death. Adjusted hazard ratios for matching-adjusted indirect comparisons were estimated via weighted Cox proportional-hazards models. Progression-free survival, using time-to-next treatment as a proxy for real-world cohorts, was summarized descriptively.
RESULTS
Distribution of baseline characteristics that were matched was similar between the GARNET cohort (n=153) and the real-world cohort (n=999). The most common International Federation of Gynecology and Obstetrics (FIGO) stage in both cohorts was stage III/IV (n=88; 57.5% and n=778; 77.9%, respectively), with endometroid histology predominating in the GARNET cohort (n=121; 79.1%) and non-endometrioid the predominant form in the real-world cohort (n=575; 57.6%). The median overall survival for dostarlimab was longer (range 27.1-40.5 months [95% confidence interval (CI) 6.4-non-estimable and 19.4-non-estimable]) both before and after matching for all scenarios compared with the real-world cohort (10.3 months). Across all matching scenarios, patients in the GARNET cohort had a decreased risk of death, with a HR for overall survival of 0.32 (p<0.0001) before matching, as compared with the overall real-world cohort and most treatment-specific real-world cohorts. For all three scenarios, progression-free survival rates at 12 and 18 months were higher for patients on dostarlimab compared with the real-world cohort (0.48 and 0.43 respectively before matching in the GARNET cohort vs 0.28 and 0.16 respectively in the real-world cohort; using time to next treatment as proxy). The effective sample size for scenario 1 was low when compared with the other scenarios (scenario 1: n=18; scenario 2: n=62; scenario 3: n=67).
CONCLUSION
In this adjusted indirect dataset, patients with recurrent/advanced mismatch repair deficient/microsatellite instability-high endometrial cancer post-platinum-based chemotherapy who received dostarlimab in the GARNET trial had significantly improved overall survival compared with patients receiving current second-line treatment in England.
Topics: Female; Humans; Platinum; Endometrial Neoplasms; Antibodies, Monoclonal, Humanized; Progression-Free Survival
PubMed: 37620100
DOI: 10.1136/ijgc-2022-004178 -
BMC Medical Genomics Jan 2023Leucine-rich repeat sequence domains are known to mediate protein‒protein interactions. Recently, some studies showed that members of the leucine rich repeat...
BACKGROUND
Leucine-rich repeat sequence domains are known to mediate protein‒protein interactions. Recently, some studies showed that members of the leucine rich repeat containing (LRRC) protein superfamily may become new targets for the diagnosis and treatment of tumours. However, it is not known whether any of the LRRC superfamily genes is expressed in the stroma of ovarian cancer (OC) and is associated with prognosis.
METHODS
The clinical data and transcriptional profiles of OC patients from the public databases TCGA (n = 427), GTEx (n = 88) and GEO (GSE40266 and GSE40595) were analysed by R software. A nomogram model was also generated through R. An online public database was used for auxiliary analysis of prognosis, immune infiltration and protein‒protein interaction (PPI) networks. Immunohistochemistry and qPCR were performed to determine the protein and mRNA levels of genes in high-grade serous ovarian cancer (HGSC) tissues of participants and the MRC-5 cell line induced by TGF-β.
RESULTS
LRRC15 and LRRC32 were identified as differentially expressed genes from the LRRC superfamily by GEO transcriptome analysis. PPI network analysis suggested that they were most enriched in TGF-β signalling. The TCGA-GTEx analysis results showed that only LRRC15 was highly expressed in both cancer-associated fibroblasts (CAFs) and the tumour stroma of OC and was related to clinical prognosis. Based on this, we developed a nomogram model to predict the incidence of adverse outcomes in OC. Moreover, LRRC15 was positively correlated with CAF infiltration and negatively correlated with CD8 + T-cell infiltration. As a single indicator, LRRC15 had the highest accuracy (AUC = 0.920) in predicting the outcome of primary platinum resistance.
CONCLUSIONS
The LRRC superfamily is related to the TGF-β pathway in the microenvironment of OC. LRRC15, as a stromal biomarker, can predict the clinical prognosis of HGSC and promote the immunosuppressive microenvironment. LRRC15 may be a potential therapeutic target for reversing primary resistance in OC.
Topics: Humans; Female; Platinum; Leucine; Ovarian Neoplasms; Prognosis; Stromal Cells; Tumor Microenvironment; Membrane Proteins
PubMed: 36653841
DOI: 10.1186/s12920-023-01435-9 -
International Journal of Molecular... Jun 2023Cisplatin (-diamminedichloroplatinum I) is a platinum-based drug, the mainstay of anticancer treatment for numerous solid tumors. Since its approval by the FDA in 1978,... (Review)
Review
Cisplatin (-diamminedichloroplatinum I) is a platinum-based drug, the mainstay of anticancer treatment for numerous solid tumors. Since its approval by the FDA in 1978, the drug has continued to be used for the treatment of half of epithelial cancers. However, resistance to cisplatin represents a major obstacle during anticancer therapy. Here, we review recent findings on how the mTORC1 pathway and autophagy can influence cisplatin sensitivity and resistance and how these data can be applicable for the development of new therapeutic strategies.
Topics: Humans; Cisplatin; Platinum; Mechanistic Target of Rapamycin Complex 1; Drug Resistance, Neoplasm; Antineoplastic Agents; Neoplasms; Autophagy
PubMed: 37445831
DOI: 10.3390/ijms241310651 -
International Journal of Molecular... Jul 2018It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never...
It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13-times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G-quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly.
Topics: Cisplatin; G-Quadruplexes; Molecular Structure; Platinum; Telomere
PubMed: 29970863
DOI: 10.3390/ijms19071951 -
Journal of Biomedical Materials... Nov 2020Silver nanoparticles (AgNPs) have been proposed to combat oral infection due to their efficient ionic silver (Ag ) release. However, concentrations required for...
Silver nanoparticles (AgNPs) have been proposed to combat oral infection due to their efficient ionic silver (Ag ) release. However, concentrations required for antimicrobial efficacy may not be therapeutically viable. In this work, platinum-doped silver nanoparticles (Pt-AgNPs) were explored to evaluate their potential for enhanced Ag release, which could lead to enhanced antimicrobial efficacy against S. aureus, P. aeruginosa, and E. coli. AgNPs doped with 0.5, 1, and 2 mol% platinum (Pt -AgNPs, Pt -AgNPs, and Pt -AgNPs) were synthesized by a chemical reduction method. Transmission electron microscopy revealed mixed morphologies of spherical, oval, and ribbon-like nanostructures. Surface-enhanced Raman scattering revealed that the surface of Pt-AgNPs was covered with up to 93% Pt. The amount of Ag released increased 16.3-fold for Pt -AgNPs, compared to AgNPs. The initial lag phase in bacterial growth curve was prolonged for Pt-AgNPs. This is consistent with a Ag release profile that exhibited an initial burst followed by sustained release. Doping AgNPs with platinum significantly increased the antimicrobial efficacy against all species. Pt -AgNPs exhibited the lowest minimum inhibitory concentrations, followed by Pt -AgNPs, Pt -AgNPs, and AgNPs, respectively. Doping AgNPs with a small amount of platinum promoted the release of Ag , based on the sacrificial anodic effect, and subsequently enhanced their antimicrobial efficacy.
Topics: Anti-Bacterial Agents; Escherichia coli; Metal Nanoparticles; Microbial Sensitivity Tests; Nanostructures; Platinum; Pseudomonas aeruginosa; Silver; Spectrum Analysis, Raman; Staphylococcus aureus
PubMed: 32618123
DOI: 10.1002/jbm.b.34674 -
International Journal of Molecular... Dec 2023Cisplatin-type covalent chemotherapeutics are a cornerstone of modern medicinal oncology. However, these drugs remain encumbered with dose-limiting side effects and are...
Cisplatin-type covalent chemotherapeutics are a cornerstone of modern medicinal oncology. However, these drugs remain encumbered with dose-limiting side effects and are susceptible to innate and acquired resistance. The bulk of platinum anticancer research has focused on Cisplatin and its derivatives. Here, we take inspiration from the design of platinum complexes and ligands used successfully with other metals to create six novel complexes. Herein, the synthesis, characterization, DNA binding affinities, and lipophilicity of a series of non-traditional organometallic Pt(II)-complexes are described. These complexes have a basic [Pt(P)(A)]Cl molecular formula which incorporates either 2-pyrrolidin-2-ylpyridine, 2-(1-Imidazol-2-yl)pyridine, or 2-(2-pyridyl)benzimidazole as the P; the A is resolved diaminocyclohexane. Precursor [Pt(P)(Cl)] complexes were also characterized for comparison. While the cytotoxicity and DNA binding properties of the three precursors were unexceptional, the corresponding [Pt(P)(A)] complexes were promising; they exhibited different DNA binding interactions compared with Cisplatin but with similar, if not slightly better, cytotoxicity results. Complexes with 2-pyrrolidin-2-ylpyridine or 2-(2-pyridyl)benzimidazole ligands had similar DNA binding properties to those with 2-(1-Imidazol-2-yl)pyridine ligands but were not as cytotoxic to all cell lines. The variation in activity between cell lines was remarkable and resulted in significant selectivity indices in MCF10A and MCF-7 breast cancer cell lines, compared with previously described similar Pt(II) complexes such as 56MESS.
Topics: Humans; Platinum; Cisplatin; Antineoplastic Agents; MCF-7 Cells; DNA; Pyridines; Ligands; Cell Line, Tumor
PubMed: 38138979
DOI: 10.3390/ijms242417150 -
PLoS Genetics Feb 2023Recently, distinct mutational footprints observed in metastatic tumors, secondary malignancies and normal human tissues have been demonstrated to be caused by the...
Recently, distinct mutational footprints observed in metastatic tumors, secondary malignancies and normal human tissues have been demonstrated to be caused by the exposure to several chemotherapeutic drugs. These characteristic mutations originate from specific lesions caused by these chemicals to the DNA of exposed cells. However, it is unknown whether the exposure to these chemotherapies leads to a specific footprint of larger chromosomal aberrations. Here, we address this question exploiting whole genome sequencing data of metastatic tumors obtained from patients exposed to different chemotherapeutic drugs. As a result, we discovered a specific copy number footprint across tumors from patients previously exposed to platinum-based therapies. This footprint is characterized by a significant increase in the number of chromosomal fragments of copy number 1-4 and size smaller than 10 Mb in exposed tumors with respect to their unexposed counterparts (median 14-387% greater across tumor types). The number of chromosomal fragments characteristic of the platinum-associated CN footprint increases significantly with the activity of the well known platinum-related footprint of single nucleotide variants across exposed tumors.
Topics: Humans; Chromosome Aberrations; DNA Copy Number Variations; Mutation; Neoplasms; Antineoplastic Agents; Platinum
PubMed: 36780550
DOI: 10.1371/journal.pgen.1010634