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Cancers May 2022Clear cell renal cell carcinoma (ccRCC) has been reported to be highly immune to and infiltrated by T cells and has angiogenesis features, but the effect of given...
Molecular Subtypes Based on Genomic and Transcriptomic Features Correlate with the Responsiveness to Immune Checkpoint Inhibitors in Metastatic Clear Cell Renal Cell Carcinoma.
Clear cell renal cell carcinoma (ccRCC) has been reported to be highly immune to and infiltrated by T cells and has angiogenesis features, but the effect of given features on clinical outcomes followed by immune checkpoint inhibitors (ICIs) in ccRCC has not been fully characterized. Currently, loss of function mutation in , a PBAF-complex gene frequently mutated in ccRCC, is associated with clinical benefit from ICIs, and is considered as a predictive biomarker for response to anti-PD-1 therapy. However, functional mechanisms of mutation regarding immunotherapy responsiveness are still poorly understood. Here, we performed targeted sequencing ( = 60) and whole transcriptomic sequencing (WTS) ( = 61) of patients with metastatic ccRCC treated by ICIs. By integrating WTS data from the CheckMate 025 trial, we obtained WTS data of 177 tumors and finally identified three molecular subtypes that are characterized by distinct molecular phenotypes and frequency of mutations. Patient clustered subtypes 1 and 3 demonstrated worse responses and survival after ICIs treatment, with a low proportion of mutation and angiogenesis-poor, but were immune-rich and cell-cycle enriched. Notably, patients clustered in the subtype 2 showed a better response and survival after ICIs treatment, with enrichment of mutation and metabolic programs and a low exhausted immune phenotype. Further analysis of the subtype 2 population demonstrated that (glycine amidinotransferase), as a novel gene associated with mutation, plays a pivotal role in ccRCC by using a cell culture model, revealing tumor, suppressive-like features in reducing proliferation and migration. In summary, we identified that metastatic ccRCC treated by ICIs have distinct genomic and transcriptomic features that may account for their responsiveness to ICIs. We also revealed that the novel gene can be a potential tumor suppressor and/or can be associated with therapeutic efficacy in metastatic ccRCC treated by ICIs.
PubMed: 35625960
DOI: 10.3390/cancers14102354 -
Cells Apr 2021The magnitude of the host immune response can be regulated by either stimulatory or inhibitory immune checkpoint molecules. Receptor-ligand binding between inhibitory... (Review)
Review
The magnitude of the host immune response can be regulated by either stimulatory or inhibitory immune checkpoint molecules. Receptor-ligand binding between inhibitory molecules is often exploited by tumours to suppress anti-tumour immune responses. Immune checkpoint inhibitors that block these inhibitory interactions can relieve T-cells from negative regulation, and have yielded remarkable activity in the clinic. Despite this success, clinical data reveal that durable responses are limited to a minority of patients and malignancies, indicating the presence of underlying resistance mechanisms. Accumulating evidence suggests that tumour hypoxia, a pervasive feature of many solid cancers, is a critical phenomenon involved in suppressing the anti-tumour immune response generated by checkpoint inhibitors. In this review, we discuss the mechanisms associated with hypoxia-mediate immunosuppression and focus on modulating tumour hypoxia as an approach to improve immunotherapy responsiveness.
Topics: Animals; Humans; Immunity; Immunosuppression Therapy; Immunotherapy; Molecular Targeted Therapy; Neoplasms; Tumor Microenvironment
PubMed: 33923305
DOI: 10.3390/cells10051006 -
Pharmaceuticals (Basel, Switzerland) Oct 2020Thanks to its innocuousness and high spatiotemporal resolution, light is used in several established and emerging applications in biomedicine. Among them is the...
Thanks to its innocuousness and high spatiotemporal resolution, light is used in several established and emerging applications in biomedicine. Among them is the modulation of magnetic resonance imaging (MRI) contrast agents' relaxivity with the aim to increase the sensitivity, selectivity and amount of functional information obtained from this outstanding whole-body medical imaging technique. This approach requires the development of molecular contrast agents that show high relaxivity and strongly pronounced photo-responsiveness. To this end, we report here the design and synthesis of a light-activated MRI contrast agent, together with its evaluation using UV-vis spectroscopy, Fast Field Cycling (FFC) relaxometry and relaxometric measurements on clinical MRI scanners. The high relaxivity of the reported agent changes substantially upon irradiation with light, showing a 17% decrease in relaxivity at 0.23T upon irradiation with λ = 400 nm (violet) light for 60 min. On clinical MRI scanners (1.5T and 3.0T), irradiation leads to a decrease in relaxivity of 9% and 19% after 3 and 60 min, respectively. The molecular design presents an important blueprint for the development of light-activatable MRI contrast agents.
PubMed: 33050049
DOI: 10.3390/ph13100296 -
Molecules (Basel, Switzerland) Jan 2023The review aims to summarize recent reports of stimuli-responsive nanomaterials based on molecularly imprinted polymers (MIPs) and discuss their applications in... (Review)
Review
The review aims to summarize recent reports of stimuli-responsive nanomaterials based on molecularly imprinted polymers (MIPs) and discuss their applications in biomedicine. In the past few decades, MIPs have been proven to show widespread applications as new molecular recognition materials. The development of stimuli-responsive nanomaterials has successfully endowed MIPs with not only affinity properties comparable to those of natural antibodies but also the ability to respond to external stimuli (stimuli-responsive MIPs). In this review, we will discuss the synthesis of MIPs, the classification of stimuli-responsive MIP nanomaterials (MIP-NMs), their dynamic mechanisms, and their applications in biomedicine, including bioanalysis and diagnosis, biological imaging, drug delivery, disease intervention, and others. This review mainly focuses on studies of smart MIP-NMs with biomedical perspectives after 2015. We believe that this review will be helpful for the further exploration of stimuli-responsive MIP-NMs and contribute to expanding their practical applications especially in biomedicine in the near future.
Topics: Molecular Imprinting; Polymers; Nanostructures; Drug Delivery Systems; Molecularly Imprinted Polymers
PubMed: 36770595
DOI: 10.3390/molecules28030918 -
BMC Cancer Mar 2022Tyrosine kinase inhibitors (TKIs) as first-line therapy for Chronic Myeloid Leukemia (CML) show a high success rate. However, a low number of patients with long-term...
Hsa-miR-181a-5p, hsa-miR-182-5p, and hsa-miR-26a-5p as potential biomarkers for BCR-ABL1 among adult chronic myeloid leukemia treated with tyrosine kinase inhibitors at the molecular response.
BACKGROUND
Tyrosine kinase inhibitors (TKIs) as first-line therapy for Chronic Myeloid Leukemia (CML) show a high success rate. However, a low number of patients with long-term treatment-free remission (TFR) were observed. Molecular relapse after imatinib discontinuation occurred at 50% at 24 months, with 80% occurrence within the first 6 months. One of the reasons for relapse is untimely TKIs discontinuation caused by large errors from estimates at very low-level or undetectable disease, thus warranting new biomarkers for CML.
METHODS
Next Generation Sequencing (NGS) was used to identify microRNAs (miRNAs) at the molecular response in CML adult patients receiving TKIs treatment. A total of 86 samples were collected, 30 from CML patients responsive and 28 from non-responsive to imatinib therapy, and 28 from blood donors. NGS was conducted whereby 18 miRNAs were selected and validated by real-time RT-qPCR in triplicate.
RESULTS
Hsa-miR-181a-5p was expressed significantly (p-value< 0.05) with 2.14 and 2.33-fold down-regulation in both patient groups, respectively meanwhile hsa-miR-182-5p and hsa-miR-26a-5p were significant only in the non-responsive group with 2.08 and 2.39 fold up-regulation. The down-regulation was consistent with decreased amounts of BCR-ABL1 in patients taking TKIs regardless of molecular responses. The up-regulation was consistent with the substantial presence of BCR-ABL1 in CML patients treated with TKIs at the molecular response.
CONCLUSIONS
Therefore, these miRNAs have potential as new therapeutic biomarkers for BCR-ABL1 status in adult CML patients treated with TKIs at molecular responses. These could improve current approaches and require further analysis to look for targets of these miRNAs in CML.
Topics: Adult; Biomarkers; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; MicroRNAs; Protein Kinase Inhibitors
PubMed: 35346116
DOI: 10.1186/s12885-022-09396-5 -
Frontiers in Plant Science 2023Drought stress affects growth and productivity significantly in chickpea. An integrated multi-omics analysis can provide a better molecular-level understanding of...
Drought stress affects growth and productivity significantly in chickpea. An integrated multi-omics analysis can provide a better molecular-level understanding of drought stress tolerance. In the present study, comparative transcriptome, proteome and metabolome analyses of two chickpea genotypes with contrasting responses to drought stress, ICC 4958 (drought-tolerant, DT) and ICC 1882 (drought-sensitive, DS), was performed to gain insights into the molecular mechanisms underlying drought stress response/tolerance. Pathway enrichment analysis of differentially abundant transcripts and proteins suggested the involvement of glycolysis/gluconeogenesis, galactose metabolism, and starch and sucrose metabolism in the DT genotype. An integrated multi-omics analysis of transcriptome, proteome and metabolome data revealed co-expressed genes, proteins and metabolites involved in phosphatidylinositol signaling, glutathione metabolism and glycolysis/gluconeogenesis pathways, specifically in the DT genotype under drought. These stress-responsive pathways were coordinately regulated by the differentially abundant transcripts, proteins and metabolites to circumvent the drought stress response/tolerance in the DT genotype. The associated genes, proteins and transcription factors may further contribute to improved drought tolerance in the DT genotype. Altogether, the multi-omics approach provided an in-depth understanding of stress-responsive pathways and candidate genes involved in drought tolerance in chickpea.
PubMed: 37287713
DOI: 10.3389/fpls.2023.1156606 -
International Journal of Molecular... Jun 2022Salt is one of the most common abiotic stresses, causing ionic and osmotic pressure changes that affect plant growth and development. In this work, we present molecular...
Salt is one of the most common abiotic stresses, causing ionic and osmotic pressure changes that affect plant growth and development. In this work, we present molecular and genetic evidence that is involved in both salt stress and in the abscisic acid response to this stress. We demonstrate that is highly induced in response to salt stress and that mutants have a lower germination rate, decreased root length, and lower survival rate compared to the wild-type in response to salt stress. Overexpression of increases expression of the salt stress-associated genes , and ABA-responsive gene . Additionally, higher levels of reactive oxygen species are detected when is overexpressed, and qRT-PCR showed that is involved in the -mediated signaling. expression is also highly induced by ABA treatment. Mutants of are hypersensitive to ABA and have a shorter root length. A decrease in water loss and reduced stomatal aperture were also observed in mutants in response to ABA. ABA-responsive genes and were downregulated in but were upregulated in the overexpression line of in response to ABA. Taken together our results suggest that modulates the response to salt stress and is involved in the ABA signaling pathway in .
Topics: Abscisic Acid; Arabidopsis; Arabidopsis Proteins; Gene Expression Regulation, Plant; Germination; Plants, Genetically Modified; Salt Stress; Stress, Physiological
PubMed: 35806295
DOI: 10.3390/ijms23137290 -
Frontiers in Plant Science 2022The effects of the climate change including an increase in the average global temperatures, and abnormal weather events such as frequent and severe heatwaves are... (Review)
Review
The effects of the climate change including an increase in the average global temperatures, and abnormal weather events such as frequent and severe heatwaves are emerging as a worldwide ecological concern due to their impacts on plant vegetation and crop productivity. In this review, the molecular processes of plants in response to heat stress-from the sensing of heat stress, the subsequent molecular cascades associated with the activation of heat shock factors and their primary targets (heat shock proteins), to the cellular responses-have been summarized with an emphasis on the classification and functions of heat shock proteins. Vegetables contain many essential vitamins, minerals, antioxidants, and fibers that provide many critical health benefits to humans. The adverse effects of heat stress on vegetable growth can be alleviated by developing vegetable crops with enhanced thermotolerance with the aid of various genetic tools. To achieve this goal, a solid understanding of the molecular and/or cellular mechanisms underlying various responses of vegetables to high temperature is imperative. Therefore, efforts to identify heat stress-responsive genes including those that code for heat shock factors and heat shock proteins, their functional roles in vegetable crops, and also their application to developing vegetables tolerant to heat stress are discussed.
PubMed: 35481144
DOI: 10.3389/fpls.2022.837152 -
Plants (Basel, Switzerland) Feb 2021The reprogramming of gene expression is one of the key responses to environmental stimuli, whereas changes in mRNA do not necessarily bring forth corresponding changes...
The reprogramming of gene expression is one of the key responses to environmental stimuli, whereas changes in mRNA do not necessarily bring forth corresponding changes of the protein, which seems partially due to the stress-induced selective translation. To address this issue, we systematically compared the transcriptome and translatome using self-produced and publicly available datasets to decipher how and to what extent the coordination and discordance between transcription and translation came to be in response to wounding (self-produced), dark to light transition, heat, hypoxia, Pi starvation and the pathogen-associated molecular pattern (elf18) in We found that changes in total mRNAs (transcriptome) and ribosome-protected fragments (translatome) are highly correlated upon dark to light transition or heat stress. However, this close correlation was generally lost under other four stresses analyzed in this study, especially during immune response, which suggests that transcription and translation are differentially coordinated under distinct stress conditions. Moreover, Gene Ontology (GO) enrichment analysis showed that typical stress responsive genes were upregulated at both transcriptional and translational levels, while non-stress-specific responsive genes were changed solely at either level or downregulated at both levels. Taking wounding responsive genes for example, typical stress responsive genes are generally involved in functional categories related to dealing with the deleterious effects caused by the imposed wounding stress, such as response to wounding, response to water deprivation and response to jasmonic acid, whereas non-stress-specific responsive genes are often enriched in functional categories like S-glycoside biosynthetic process, photosynthesis and DNA-templated transcription. Collectively, our results revealed the differential as well as targeted coordination between transcriptome and translatome in response to diverse stresses, thus suggesting a potential model wherein preferential ribosome loading onto the stress-upregulated mRNA pool could be a pacing factor for selective translation.
PubMed: 33562590
DOI: 10.3390/plants10020304 -
Frontiers in Plant Science 2021A growing body of evidence indicates that extracellular fragmented self-DNA (eDNA), by acting as a signaling molecule, triggers inhibitory effects on conspecific plants...
A growing body of evidence indicates that extracellular fragmented self-DNA (eDNA), by acting as a signaling molecule, triggers inhibitory effects on conspecific plants and functions as a damage-associated molecular pattern (DAMP). To evaluate early and late events in DAMP-dependent responses to eDNA, we extracted, fragmented, and applied the tomato () eDNA to tomato leaves. Non-sonicated, intact self-DNA (intact DNA) was used as control. Early event analyses included the evaluation of plasma transmembrane potentials (Vm), cytosolic calcium variations (Ca ), the activity and subcellular localization of both voltage-gated and ligand-gated rectified K channels, and the reactive oxygen species (ROS) subcellular localization and quantification. Late events included RNA-Seq transcriptomic analysis and qPCR validation of gene expression of tomato leaves exposed to tomato eDNA. Application of eDNA induced a concentration-dependent Vm depolarization which was correlated to an increase in (Ca); this event was associated to the opening of K channels, with particular action on ligand-gated rectified K channels. Both eDNA-dependent (Ca) and K increases were correlated to ROS production. In contrast, application of intact DNA produced no effects. The plant response to eDNA was the modulation of the expression of genes involved in plant-biotic interactions including pathogenesis-related proteins (PRPs), calcium-dependent protein kinases (CPK1), heat shock transcription factors (Hsf), heat shock proteins (Hsp), receptor-like kinases (RLKs), and ethylene-responsive factors (ERFs). Several genes involved in calcium signaling, ROS scavenging and ion homeostasis were also modulated by application of eDNA. Shared elements among the transcriptional response to eDNA and to biotic stress indicate that eDNA might be a common DAMP that triggers plant responses to pathogens and herbivores, particularly to those that intensive plant cell disruption or cell death. Our results suggest the intriguing hypothesis that some of the plant reactions to pathogens and herbivores might be due to DNA degradation, especially when associated to the plant cell disruption. Fragmented DNA would then become an important and powerful elicitor able to trigger early and late responses to biotic stress.
PubMed: 34381477
DOI: 10.3389/fpls.2021.686121