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Nature Cell Biology May 2024
PubMed: 38641662
DOI: 10.1038/s41556-024-01417-8 -
PloS One 2024Many oncology antibody-drug conjugates (ADCs) have failed to demonstrate efficacy in clinic because of dose-limiting toxicity caused by uptake into healthy tissues. We...
Many oncology antibody-drug conjugates (ADCs) have failed to demonstrate efficacy in clinic because of dose-limiting toxicity caused by uptake into healthy tissues. We developed an approach that harnesses ADC affinity to broaden the therapeutic index (TI) using two anti-mesenchymal-epithelial transition factor (MET) monoclonal antibodies (mAbs) with high affinity (HAV) or low affinity (LAV) conjugated to monomethyl auristatin E (MMAE). The estimated TI for LAV-ADC was at least 3 times greater than the HAV-ADC. The LAV- and HAV-ADCs showed similar levels of anti-tumor activity in the xenograft model, while the 111In-DTPA studies showed similar amounts of the ADCs in HT29 tumors. Although the LAV-ADC has ~2-fold slower blood clearance than the HAV-ADC, higher liver toxicity was observed with HAV-ADC. While the SPECT/CT 111In- and 124I- DTPA findings showed HAV-ADC has higher accumulation and rapid clearance in normal tissues, intravital microscopy (IVM) studies confirmed HAV mAb accumulates within hepatic sinusoidal endothelial cells while the LAV mAb does not. These results demonstrated that lowering the MET binding affinity provides a larger TI for MET-ADC. Decreasing the affinity of the ADC reduces the target mediated drug disposition (TMDD) to MET expressed in normal tissues while maintaining uptake/delivery to the tumor. This approach can be applied to multiple ADCs to improve the clinical outcomes.
Topics: Humans; Animals; Pharmaceutical Preparations; Iodine Radioisotopes; Endothelial Cells; Cell Line, Tumor; Immunoconjugates; Pentetic Acid; Xenograft Model Antitumor Assays
PubMed: 38630694
DOI: 10.1371/journal.pone.0293703 -
Hellenic Journal of Nuclear Medicine 2024Recently, gallium-68-prostate-specific membrane antigen-11 (Ga-PSMA-11) positron emission tomography/computed tomography (PET/CT) has become a key imaging method in...
A pictorial view on false positive findings of Ga-PSMA-11 PET/CT and their prognostic value in patients with prostate carcinoma after radical prostatectomy and undetectable PSA values.
OBJECTIVE
Recently, gallium-68-prostate-specific membrane antigen-11 (Ga-PSMA-11) positron emission tomography/computed tomography (PET/CT) has become a key imaging method in prostate carcinoma staging and biochemical progression, with varying sensitivities in different studies (from 40% to 80%). After four years of experience with Ga-PSMA-11 PET/CT, we found that it is possible to detect lesions with increased PSMA expression in patients with undetectable prostate specific antigen (PSA) levels after radical prostatectomy. The key questions we wanted to answer were as follows: if those lesions were malignant and could the early detection of those malignant lesions have a role in patient management? We aimed to identify and follow up PSMA-positive findings for a period of 4 years in patients with prostate cancer after radical prostatectomy and undetectable PSA values at the time of the examination. We also explored false-positive lesions in detail.
SUBJECTS AND METHODS
The study included all patients who underwent radical prostatectomy and had undetectable PSA values <0.05ng/mL and who underwent Ga-PSMA-11 PET/CT between July 2019 and December 2019. We performed 220 studies and found 40 patients with these characteristics; these patients were included in this study. All of them were followed up until July 2023. Any finding with increased radiopharmaceutical accumulation above the background activity in the respective area was considered a false positive. Prostate-specific membrane antigen accumulation in established lesions was assessed semi-quantitatively by the maximum standardized uptake value (SUVmax) and qualitatively by the four-point visual scale proposed in the E-PSMA recommendations.
RESULTS
We found 15/40 (37.5%) patients with PSMA-positive findings. These were predominantly bone changes without a corresponding CT abnormality or discrete cystic or osteoblastic lesions with above-background increased PSMA expression. The mean SUVmax of these non-specific lesions was 3.02 (SD 2.86). After 3.5-4 years of follow-up, biochemical progression was found in only two of the patients.The great sensitivity of the method nowadays is a powerful engine for the development of new therapeutic options. On the other side, the lower specificity due to false positive findings, if misinterpreted, might lead to switching to a higher stage, with the planned radical treatment replaced by palliative treatment.
CONCLUSION
The presence of Ga-PSMA-11 PET/CT-positive findings in patients after radical prostatectomy and an undetectable PSA had a low predictive value for future progression. The interpretation of Ga-PSMA-11 PET/CT should always include a complex assessment of the clinical setting-the risk group, PSA value and degree of PSMA accumulation in the lesions. In these situations, further clarification of PSMA-positive findings is appropriate before deciding to change treatment.
Topics: Aged; Humans; Male; Middle Aged; Edetic Acid; False Positive Reactions; Gallium Isotopes; Gallium Radioisotopes; Oligopeptides; Positron Emission Tomography Computed Tomography; Prognosis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms
PubMed: 38629815
DOI: 10.1967/s002449912702 -
BMC Genomics Apr 2024Quinoa (Chenopodium quinoa Willd.) is valued for its nutritional richness. However, pre-harvest sprouting poses a significant threat to yield and grain quality. This...
BACKGROUND
Quinoa (Chenopodium quinoa Willd.) is valued for its nutritional richness. However, pre-harvest sprouting poses a significant threat to yield and grain quality. This study aims to enhance our understanding of pre-harvest sprouting mitigation strategies, specifically through delayed sowing and avoiding rainy seasons during quinoa maturation. The overarching goal is to identify cold-resistant varieties and unravel the molecular mechanisms behind the low-temperature response of quinoa. We employed bioinformatics and genomics tools for a comprehensive genome-wide analysis of polyamines (PAs) and ethylene synthesis gene families in quinoa under low-temperature stress.
RESULTS
This involved the identification of 37 PA biosynthesis and 30 PA catabolism genes, alongside 227 ethylene synthesis. Structural and phylogenetic analyses showcased conserved patterns, and subcellular localization predictions indicated diverse cellular distributions. The results indicate that the PA metabolism of quinoa is closely linked to ethylene synthesis, with multiple genes showing an upregulation in response to cold stress. However, differential expression within gene families suggests a nuanced regulatory network.
CONCLUSIONS
Overall, this study contributes valuable insights for the functional characterization of the PA metabolism and ethylene synthesis of quinoa, which emphasize their roles in plant low-temperature tolerance and providing a foundation for future research in this domain.
Topics: Chenopodium quinoa; Phylogeny; Temperature; Polyamines; Ethylenes
PubMed: 38627628
DOI: 10.1186/s12864-024-10265-7 -
Cardiovascular Research May 2024Potential loss-of-function variants of ATP13A3, the gene encoding a P5B-type transport ATPase of undefined function, were recently identified in patients with pulmonary...
AIMS
Potential loss-of-function variants of ATP13A3, the gene encoding a P5B-type transport ATPase of undefined function, were recently identified in patients with pulmonary arterial hypertension (PAH). ATP13A3 is implicated in polyamine transport but its function has not been fully elucidated. In this study, we sought to determine the biological function of ATP13A3 in vascular endothelial cells (ECs) and how PAH-associated variants may contribute to disease pathogenesis.
METHODS AND RESULTS
We studied the impact of ATP13A3 deficiency and overexpression in EC models [human pulmonary ECs, blood outgrowth ECs (BOECs), and human microvascular EC 1], including a PAH patient-derived BOEC line harbouring an ATP13A3 variant (LK726X). We also generated mice harbouring an Atp13a3 variant analogous to a human disease-associated variant to establish whether these mice develop PAH. ATP13A3 localized to the recycling endosomes of human ECs. Knockdown of ATP13A3 in ECs generally reduced the basal polyamine content and altered the expression of enzymes involved in polyamine metabolism. Conversely, overexpression of wild-type ATP13A3 increased polyamine uptake. Functionally, loss of ATP13A3 was associated with reduced EC proliferation, increased apoptosis in serum starvation, and increased monolayer permeability to thrombin. The assessment of five PAH-associated missense ATP13A3 variants (L675V, M850I, V855M, R858H, and L956P) confirmed loss-of-function phenotypes represented by impaired polyamine transport and dysregulated EC function. Furthermore, mice carrying a heterozygous germline Atp13a3 frameshift variant representing a human variant spontaneously developed a PAH phenotype, with increased pulmonary pressures, right ventricular remodelling, and muscularization of pulmonary vessels.
CONCLUSION
We identify ATP13A3 as a polyamine transporter controlling polyamine homeostasis in ECs, a deficiency of which leads to EC dysfunction and predisposes to PAH. This suggests a need for targeted therapies to alleviate the imbalances in polyamine homeostasis and EC dysfunction in PAH.
Topics: Animals; Humans; Polyamines; Endothelial Cells; Cell Proliferation; Pulmonary Artery; Proton-Translocating ATPases; Pulmonary Arterial Hypertension; Apoptosis; Hypertension, Pulmonary; Endosomes; Biological Transport; Disease Models, Animal; Cells, Cultured; Phenotype; Mice, Inbred C57BL; Mice
PubMed: 38626311
DOI: 10.1093/cvr/cvae068 -
Nucleic Acids Research May 2024Antisense oligonucleotide (ASO) therapy is a novel therapeutic approach in which ASO specifically binds target mRNA, resulting in mRNA degradation; however, cellular...
Antisense oligonucleotide (ASO) therapy is a novel therapeutic approach in which ASO specifically binds target mRNA, resulting in mRNA degradation; however, cellular uptake of ASOs remains critically low, warranting improvement. Transient receptor potential canonical (TRPC) channels regulate Ca2+ influx and are activated upon stimulation by phospholipase C-generated diacylglycerol. Herein, we report that a novel TRPC3/C6/C7 activator, L687, can induce cellular ASO uptake. L687-induced ASO uptake was enhanced in a dose- and incubation-time-dependent manner. L687 enhanced the knockdown activity of various ASOs both in vitro and in vivo. Notably, suppression of TRPC3/C6 by specific siRNAs reduced ASO uptake in A549 cells. Application of BAPTA-AM, a Ca2+ chelator, and SKF96365, a TRPC3/C6 inhibitor, suppressed Ca2+ influx via TRPC3/C6, resulting in reduced ASO uptake, thereby suggesting that Ca2+ influx via TRPC3/C6 is critical for L687-mediated increased ASO uptake. L687 also induced dextran uptake, indicating that L687 increased endocytosis. Adding ASO to L687 resulted in endosome accumulation; however, the endosomal membrane disruptor UNC7938 facilitated endosomal escape and enhanced knockdown activity. We discovered a new function for TRPC activators regarding ASO trafficking in target cells. Our findings provide an opportunity to formulate an innovative drug delivery system for the therapeutic development of ASO.
Topics: Humans; Oligonucleotides, Antisense; TRPC Cation Channels; Calcium; A549 Cells; Animals; Mice; Imidazoles; TRPC6 Cation Channel; Egtazic Acid; Endosomes; Cell Line, Tumor
PubMed: 38621757
DOI: 10.1093/nar/gkae245 -
International Journal of Nanomedicine 2024Natural nanoparticles have been found to exist in traditional Chinese medicine (TCM) decoctions. However, whether natural nanoparticles can influence the oral...
BACKGROUND
Natural nanoparticles have been found to exist in traditional Chinese medicine (TCM) decoctions. However, whether natural nanoparticles can influence the oral bioavailability of active compounds has not been elucidated. Using Xie-Bai-San decoction (XBSD) as an example, the purpose of this study was to isolate, characterize and elucidate the mechanism of the nanoparticles (N-XBSD) in XBSD, and further to explore whether the bioavailability of the main active compounds could be enhanced by N-XBSD.
METHODS
N-XBSD were isolated from XBSD, and investigated its characterization and study of its formation mechanism, and evaluation of its ability to enhance bioavailability of active compounds.
RESULTS
The N-XBSD was successfully isolated with the average particle size of 104.53 nm, PDI of 0.27 and zeta potential of -5.14 mV. Meanwhile, all the eight active compounds were most presented in N-XBSD. Kukoamine B could self-assemble with mulberroside A or liquiritin to form nanoparticles, respectively. And the FT-IR and HRMS results indicated the possible binding of the ammonium group of kukoamine B with the phenolic hydroxyl group of mulberroside A or liquiritin, respectively. The established UPLC-MS/MS method was accurate and reliable and met the quantitative requirements. The pharmacokinetic behaviors of the N-XBSD and decoction were similar in rats. Most notably, compared to that of free drugs, the , AUC, AUC, and MRT values of index compounds were the higher in N-XBSD, with a slower plasma clearance rate in rats.
CONCLUSION
The major active compounds of XBSD were mainly distributed in N-XBSD, and N-XBSD was formed through self-assembly among active compounds. N-XBSD could obviously promote the bioavailability of active compounds, indicating natural nanoparticles of decoctions play an important role in therapeutic effects.
Topics: Animals; Rats; Biological Availability; Chromatography, Liquid; Spectroscopy, Fourier Transform Infrared; Tandem Mass Spectrometry; Nanoparticles; Caffeic Acids; Disaccharides; Spermine; Stilbenes
PubMed: 38617795
DOI: 10.2147/IJN.S449268 -
International Journal of Medical... 2024Dysregulation of cellular metabolism is a key marker of cancer, and it is suggested that metabolism should be considered as a targeted weakness of colorectal cancer....
Dysregulation of cellular metabolism is a key marker of cancer, and it is suggested that metabolism should be considered as a targeted weakness of colorectal cancer. Increased polyamine metabolism is a common metabolic change in tumors. Thus, targeting polyamine metabolism for anticancer therapy, particularly polyamine blockade therapy, has gradually become a hot topic. Quercetin-3-methyl ether is a natural compound existed in various plants with diverse biological activities like antioxidant and antiaging. Here, we reported that Quercetin-3-methyl ether inhibits colorectal cancer cell viability, and promotes apoptosis in a dose-dependent and time-dependent manner. Intriguingly, the polyamine levels, including spermidine and spermine, in colorectal cancer cells were reduced upon treatment of Quercetin-3-methyl ether. This is likely resulted from the downregulation of SMOX, a key enzyme in polyamine metabolism that catalyzes the oxidation of spermine to spermidine. These findings suggest Quercetin-3-methyl ether decreases cellular polyamine level by suppressing SMOX expression, thereby inducing colorectal cancer cell apoptosis. Our results also reveal a correlation between the anti-tumor activity of Quercetin-3-methyl ether and the polyamine metabolism modulation, which may provide new insights into a better understanding of the pharmacological activity of Quercetin-3-methyl ether and how it reprograms cellular polyamine metabolism.
Topics: Humans; Polyamines; Spermidine; Spermine; Apoptosis; Biological Products; Colorectal Neoplasms; Quercetin
PubMed: 38617002
DOI: 10.7150/ijms.93903 -
International Journal of Molecular... Apr 2024D-arginine (D-Arg) can promote embryogenic callus (EC) proliferation and increase the rate of somatic embryo induction of litchi ( Sonn.), yet the mechanism underlying...
Physiological, Metabolic, and Transcriptomic Analyses Reveal Mechanisms of Proliferation and Somatic Embryogenesis of Litchi ( Sonn.) Embryogenic Callus Promoted by D-Arginine Treatment.
D-arginine (D-Arg) can promote embryogenic callus (EC) proliferation and increase the rate of somatic embryo induction of litchi ( Sonn.), yet the mechanism underlying the processes is incompletely understood. To investigate the mechanism, physiological responses of polyamines (PAs) [putrescine (Put), spermidine (Spd), and spermine (Spm)] were investigated for D-Arg-treated litchi EC and enzyme activity related to polyamine metabolism, plant endogenous hormones, and polyamine- and embryogenic-related genes were explored. Results showed that the exogenous addition of D-Arg reduces the activity of diamine oxidase (DAO) and polyamine oxidase (PAO) in EC, reduces the production of HO, promotes EC proliferation, and increases the (Spd + Spm)/Put ratio to promote somatic embryo induction. Exogenous D-Arg application promoted somatic embryogenesis (SE) by increasing indole-3-acetyl glycine (IAA-Gly), kinetin-9-glucoside (K9G), and dihydrozeatin-7-glucoside (DHZ7G) levels and decreasing trans-zeatin riboside (tZR), N-[(-)-jasmonoyl]-(L)-valine (JA-Val), jasmonic acid (JA), and jasmonoyl-L-isoleucine (Ja-ILE) levels on 18 d, as well as promoting cell division and differentiation. The application of exogenous D-Arg regulated EC proliferation and somatic embryo induction by altering gene expression levels of the WRKY family, AP2/ERF family, C3H family, and C2H2 family. These results indicate that exogenous D-Arg could regulate the proliferation of EC and the SE induction of litchi by changing the biosynthesis of PAs through the alteration of gene expression pattern and endogenous hormone metabolism.
Topics: Litchi; Hydrogen Peroxide; Embryonic Development; Polyamines; Spermidine; Putrescine; Spermine; Arginine; Cell Division; Glucosides; Cyclopentanes; Isoleucine; Oxylipins
PubMed: 38612774
DOI: 10.3390/ijms25073965 -
Plants (Basel, Switzerland) Mar 2024Milpa is an agroecological production system based on the polyculture of plant species, with corn featuring as a central component. Traditionally, the milpa system does...
Milpa is an agroecological production system based on the polyculture of plant species, with corn featuring as a central component. Traditionally, the milpa system does not require the application of chemicals, and so pest attacks and poor growth in poor soils can have adverse effects on its production. Therefore, the application of bioinoculants could be a strategy for improving crop growth and health; however, the effect of external inoculant agents on the endemic microbiota associated with corn has not been extensively studied. Here, the objective of this work was to fertilize a maize crop under a milpa agrosystem with the PGPR UM270, evaluating its impact on the diversity of the rhizosphere (rhizobiome) and root endophytic (root endobiome) microbiomes of maize plants. The endobiome of maize roots was evaluated by 16S rRNA and internal transcribed spacer region (ITS) sequencing, and the rhizobiome was assessed by metagenomic sequencing upon inoculation with the strain UM270. The results showed that UM270 inoculation of the rhizosphere of UM270 did not increase alpha diversity in either the monoculture or milpa, but it did alter the endophytic microbiome of maize plant roots by stimulating the presence of bacterial operational taxonomic units (OTUs) of the genera and (in a monoculture), whereas, in the milpa system, the PGPR stimulated greater endophytic diversity and the presence of genera such as , , and N-fixing rhizobia genera, including , , and . No clear association was found between fungal diversity and the presence of strain UM270, but beneficial fungi, such as and , were detected in the Milpa system. In addition, network analysis revealed unique interactions with species such as sp., , and , which could potentially play beneficial roles in the plant. Finally, the UM270 strain does not seem to have a strong impact on the microbial diversity of the rhizosphere, but it does have a strong impact on some functions, such as trehalose synthesis, ammonium assimilation, and polyamine metabolism. The inoculation of UM270 biofertilizer in maize plants modifies the rhizo- and endophytic microbiomes with a high potential for stimulating plant growth and health in agroecological crop models.
PubMed: 38611483
DOI: 10.3390/plants13070954