Purpose: The clinical application of PD-L1 immunohistochemistry (IHC) testing is complicated by the availability of multiple IHC assays, scoring algorithms, and cutoffs. This study assessed the analytical comparability of three commercially available PD-L1 assays and two scoring algorithms used to assess PD-L1 status in gastric cancer (GC) samples.
Methods: Serial sections of 100 resected GC samples, with PD-L1 expression levels across the dynamic range, were stained with three in vitro diagnostic-grade PD-L1 assays (28-8, 22C3, and SP263).
High levels of IL1β can result in chronic inflammation, which in turn can promote tumor growth and metastasis. Inhibition of IL1β could therefore be a promising therapeutic option in the treatment of cancer. Here, the effects of IL1β blockade induced by the mAbs canakinumab and gevokizumab were evaluated alone or in combination with docetaxel, anti-programmed cell death protein 1 (anti-PD-1), anti-VEGFα, and anti-TGFβ treatment in syngeneic and humanized mouse models of cancers of different origin.
View Article and Find Full Text PDFNowadays, magnetoelectric nanomaterials are on their way to finding wide applications in biomedicine for various cancer and neurological disease treatment, which is mainly restricted by their relatively high toxicity and complex synthesis. This study for the first time reports novel magnetoelectric nanocomposites of CoFeO-BaTiO series with tuned magnetic phase structures, which were synthesized via a two-step chemical approach in polyol media. The magnetic CoFeO phases with x = 0.
View Article and Find Full Text PDFRedox-responsive and magnetic nanomaterials are widely used in tumor treatment separately, and while the application of their combined functionalities is perspective, exactly how such synergistic effects can be implemented is still unclear. This report investigates the internalization dynamics of magnetic redox-responsive nanoparticles (MNP-SS) and their cytotoxicity toward PC-3 and 4T1 cell lines. It is shown that MNP-SS synthesized by covalent grafting of polyethylene glycol (PEG) on the magnetic nanoparticle (MNP) surface via SS-bonds lose their colloidal stability and aggregate fully in a solution containing DTT, and partially in conditioned media, whereas the PEGylated MNP (MNP-PEG) without S-S linker control remains stable under the same conditions.
View Article and Find Full Text PDFUnlabelled: It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator.
View Article and Find Full Text PDFACS Omega
June 2022
Enzymes conjugated to magnetic nanoparticles (MNPs) undergo changes in the catalytic activity of the non-heating low-frequency magnetic field (LFMF). We apply in silico simulations by molecular dynamics (MD) and in vitro spectroscopic analysis of the enzyme kinetics and secondary structure to study α-chymotrypsin (CT) conjugated to gold-coated iron oxide MNPs. The latter are functionalized by either carboxylic or amino group moieties to vary the points of enzyme attachment.
View Article and Find Full Text PDFBackground: The randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.
Methods: In COMBI-i (ClinicalTrials.
Purpose: Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.
View Article and Find Full Text PDFSolid solution AuFe nanoparticles were synthesized for the first time under ambient conditions by an adapted method previously established for the FeO-Au core-shell morphology. These AuFe particles preserved the fcc structure of Au incorporated with paramagnetic Fe atoms. The metastable AuFe can be segregated by transformation into Janus Au/Fe particles with bcc Fe and fcc Au upon annealing.
View Article and Find Full Text PDFIron oxide nanoparticles (IONs) are frequently used in various biomedical applications, in particular as magnetic resonance imaging contrast agents in liver imaging. Indeed, number of IONs have been withdrawn due to their poor clinical performance. Yet comprehensive understanding of their interactions with hepatocytes remains relatively limited.
View Article and Find Full Text PDFThe chemical synthesis of nanoparticles with a preassigned size and shape is important for an optimized performance in any application. Therefore, systematic monitoring of the synthesis is required for the control and detailed understanding of the nucleation and growth of the nanoparticles. Here, we study Fe3O4-Au hybrid nanoparticles in detail using probes of the reaction mixture during synthesis and their thorough characterization.
View Article and Find Full Text PDFMagnetic hyperthermia (MHT) is a promising approach for cancer therapy. However, a systematic MHT characterization as function of temperature on the therapeutic efficiency is barely analyzed. Here, we first perform comparative temperature-dependent analysis of the cobalt ferrite nanoparticles-mediated MHT effectiveness in two murine tumors models - breast (4T1) and colon (CT26) cancer in vitro and in vivo.
View Article and Find Full Text PDFBackground: For the advancement of cancer research, the collection of tissue specimens from drug-resistant tumors after targeted therapy is crucial. Although patients with lung cancer are often provided targeted therapy, post-therapy specimens are not routinely collected due to the risks of collection, limiting the study of targeted therapy resistance mechanisms. Posthumous rapid tissue donation (RTD) is an expedient collection process that provides an opportunity to understand treatment-resistant lung cancers.
View Article and Find Full Text PDFSize-selected FeO-Au hybrid nanoparticles with diameters of 6-44 nm (FeO) and 3-11 nm (Au) were prepared by high temperature, wet chemical synthesis. High-quality FeO nanocrystals with bulk-like magnetic behavior were obtained as confirmed by the presence of the Verwey transition. The 25 nm diameter FeO-Au hybrid nanomaterial sample (in aqueous and agarose phantom systems) showed the best characteristics for application as contrast agents in magnetic resonance imaging and for local heating using magnetic particle hyperthermia.
View Article and Find Full Text PDFHerein, we report a novel one-step solvothermal synthesis of magnetite nanoclusters (MNCs). In this report, we discuss the synthesis, structure, and properties of MNCs and contrast enhancement in T-weighted MR images using magnetite nanoclusters. The effect of different organic acids, used as surfactants, on the size and shape of MNCs was investigated.
View Article and Find Full Text PDFAging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis.
View Article and Find Full Text PDFScaffold modification based on Wang's pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3'-pyrrolidin]-2(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3S,3'S,3'aS,5'R,6'aS)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-2-oxo-1,2,3',3'a,4',5',6',6'a-octahydro-1'H-spiro[indole-3,2'-pyrrolo[3,2-b]pyrrole]-5'-yl]benzoic acid (BI-0252).
View Article and Find Full Text PDFInhibition of the IGF1R, INSRA, and INSRB receptor tyrosine kinases represents an attractive approach of pharmacologic intervention in cancer, owing to the roles of the IGF1R and INSRA in promoting cell proliferation and survival. However, the central role of the INSRB isoform in glucose homeostasis suggests that prolonged inhibition of this kinase could result in metabolic toxicity. We describe here the profile of the novel compound BI 885578, a potent and selective ATP-competitive IGF1R/INSR tyrosine kinase inhibitor distinguished by rapid intestinal absorption and a short in vivo half-life as a result of rapid metabolic clearance.
View Article and Find Full Text PDFSix new triterpene glycosides, cladolosides Al-A6 (1-6), have been isolated from the Vietnamese sea cucumber Cladolabes schmeltzii (Cladolabinae, Sclerodactylidae, Dendrochirotida). Structures of the glycosides were elucidated by 2D NMR spectroscopy and MS. All the glycosides have nonsulfated tetrasaccharide linear carbohydrate moieties.
View Article and Find Full Text PDFEpimeric (20R,23R)- and (20R,23S)-23-hydroxycholestane steroids were synthesized. Their structures were elucidated by extensive 1H and 13C NMR spectroscopy and application of the Mosher's method. All proton and carbon signals of the side chains were assigned.
View Article and Find Full Text PDFInnate immune cells play a major role in the early response to myocardial ischemia/reperfusion (MI/R) injury. Recombinant human ADAMTS13 (rhADAMTS13), cleaving von Willebrand factor (VWF), reduces leukocyte recruitment in mice. Death of cardiomyocytes and the possible formation of neutrophil extracellular traps (NETs) may result in chromatin release that is prothrombotic and cytotoxic.
View Article and Find Full Text PDFObjective: Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps. This extracellular DNA exerts potent proinflammatory, prothrombotic, and cytotoxic properties.
View Article and Find Full Text PDFCoronary heart disease is a major cause of death in the western world. Although essential for successful recovery, reperfusion of ischemic myocardium is inevitably associated with reperfusion injury. To investigate a potential protective role of ADAMTS13, a protease cleaving von Willebrand factor multimers, during myocardial ischemia/reperfusion, we used a mouse model of acute myocardial infarction.
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