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Cancer Research Jun 2024Colorectal cancer (CRC) is the second most common malignant tumor world-wide. Analysis of the changes that occur during CRC progression could provide insights into the...
Colorectal cancer (CRC) is the second most common malignant tumor world-wide. Analysis of the changes that occur during CRC progression could provide insights into the molecular mechanisms driving CRC development and identify improved treatment strategies. Here, we performed an integrated multi-omics analysis of 435 trace-tumor-samples from 148 colorectal cancer (CRC) patients, covering non-tumor (NT), intraepithelial neoplasia (IEN), infiltration (IFT), and advanced-stage CRC (A-CRC) phases. Proteogenomics analyses demonstrated that KRAS and BRAF mutations were mutually exclusive and elevated oxidation phosphorylation in the IEN phase. Chr17q loss and chr20q gain were also mutually exclusive, occurred predominantly in the IEN and IFT phases, respectively, and impacted the cell cycle. Mutation of TP53 was frequent in the A-CRC phase and associated with tumor microenvironment, including increased extracellular matrix rigidity and stromal infiltration. Analysis of the profiles of CRC based on CMS and CRIS classifications revealed the progression paths of each subtype and indicated that microsatellite instability was associated with specific subtype classifications. Additional comparison of molecular characteristics of CRC based on location showed that ANKRD22 amplification by chr10q23.31 gain enhanced glycolysis in the right-sided CRC. The AOM/DSS-induced CRC carcinogenesis mouse model in mice indicated that DDX5 deletion due to chr17q loss promoted CRC development, consistent with the findings from the patient samples. Collectively, this study provides an informative resource for understanding the driving events of different stages of CRC and identifying the potential therapeutic targets.
PubMed: 38861363
DOI: 10.1158/0008-5472.CAN-23-1878 -
Blood Science (Baltimore, Md.) Jul 2024Tissue-resident memory T (TRM) cells infiltrating solid tumors could influence tumor progression and the response to immune therapies. However, the proportion and...
Tissue-resident memory T (TRM) cells infiltrating solid tumors could influence tumor progression and the response to immune therapies. However, the proportion and prognostic value of TRM cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) are unclear. In this study, we used flow cytometry to assay the phenotype of 49 BM samples from patients newly diagnosed with AML (ND-AML). We found that the BM CD8 effector memory (TEM) cells highly expressed CD69 (CD8 TRM-like T cells), and their percentage was significantly increased in patients with ND-AML compared with that in healthy individuals (HI). The high percentage of CD8 TRM-like subset was associated with poor overall survival in our ND-AML cohort. The Kaplan-Meier Plotter database verified a significantly reduced survival rate among patients with high expression of CD8 TRM-like T cell characteristic genes (, , and ), especially the M4 and M5 subtypes. Phenotypic analysis revealed that the BM CD8 TRM-like subpopulation exhibited exhausted T cell characteristics, but its high expression of CD27 and CD28 and low expression of CD57 suggested its high proliferative potential. The single-cell proteogenomic dataset confirmed the existence of TRM-like CD8 T cells in the BM of patients with AML and verified the high expression of immune checkpoints and costimulatory molecules. In conclusion, we found that the accumulation of BM CD8 TRM-like cells could be an immune-related survival prediction marker for patients with AML.
PubMed: 38854481
DOI: 10.1097/BS9.0000000000000194 -
Cancer Science Jun 2024Ubiquitin-specific peptidase 15 (USP15), a critical deubiquitinating enzyme, has been demonstrated to improve substrate stabilization by hydrolyzing the bond between the...
Ubiquitin-specific peptidase 15 (USP15), a critical deubiquitinating enzyme, has been demonstrated to improve substrate stabilization by hydrolyzing the bond between the substrate and ubiquitin, and is implicated in multiple carcinogenic processes. Prompted by the information cited from The Cancer Genome Atlas (TCGA) database and the Cancer Proteogenomic Data Analysis Site (cProSite), USP15 is selectively overexpressed in clear cell renal cell carcinoma (ccRCC) samples. We aimed to investigate the function of USP15 on ccRCC malignant features, which was emphasized in its deubiquitination of SHC adaptor protein 1 (SHC1). The overexpression of USP15 promoted the capacity of proliferation, migration, and invasion in ccRCC CAKI1 and 769-P cells, and these malignant biological properties were diminished by USP15 deletion in 786-O cells. USP15 accelerated tumor growth and lung metastasis in vivo. In addition, deubiquitinase USP15 was further identified as a new protector for SHC1 from degradation by the ubiquitination pathway, the post-translational modification. In sequence, transcription factor activating enhancer binding protein 4 (TFAP4) was shown to be partly responsible for USP15 expression at the level of transcription, as manifested by the chromatin immunoprecipitation and pull-down assay. Based on the in vitro and in vivo data, we postulate that USP15 regulated by TFAP4 transcriptionally deteriorates ccRCC malignant biological properties via stabilizing SHC1 by deubiquitination.
PubMed: 38847328
DOI: 10.1111/cas.16237 -
Nature Communications Jun 2024The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26...
The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.
Topics: Animals; Female; Humans; Mice; Cell Line, Tumor; Cell Proliferation; Chromosomes, Human, Pair 3; Gene Expression Regulation, Leukemic; Histone Deacetylase Inhibitors; Leukemia, Myeloid, Acute; MDS1 and EVI1 Complex Locus Protein; Proteogenomics; Proto-Oncogene Proteins c-myc; Xenograft Model Antitumor Assays
PubMed: 38834613
DOI: 10.1038/s41467-024-48953-3 -
Tropical Animal Health and Production Jun 2024Proteomics, the large-scale study of proteins in biological systems has emerged as a pivotal tool in the field of animal and veterinary sciences, mainly for... (Review)
Review
Proteomics, the large-scale study of proteins in biological systems has emerged as a pivotal tool in the field of animal and veterinary sciences, mainly for investigating local and rustic breeds. Proteomics provides valuable insights into biological processes underlying animal growth, reproduction, health, and disease. In this review, we highlight the key proteomics technologies, methodologies, and their applications in domestic animals, particularly in the tropical context. We also discuss advances in proteomics research, including integration of multi-omics data, single-cell proteomics, and proteogenomics, all of which are promising for improving animal health, adaptation, welfare, and productivity. However, proteomics research in domestic animals faces challenges, such as sample preparation variation, data quality control, privacy and ethical considerations relating to animal welfare. We also provide recommendations for overcoming these challenges, emphasizing the importance of following best practices in sample preparation, data quality control, and ethical compliance. We therefore aim for this review to harness the full potential of proteomics in advancing our understanding of animal biology and ultimately improve animal health and productivity in local breeds of diverse animal species in a tropical context.
Topics: Animals; Proteomics; Animal Husbandry; Tropical Climate; Animals, Domestic
PubMed: 38825622
DOI: 10.1007/s11250-024-04037-4 -
Clinical & Translational Oncology :... May 2024This study aimed to identify potential subtypes of hepatocellular carcinoma (HCC) associated with cirrhosis and to investigate key markers using bioinformatic analysis...
BACKGROUND
This study aimed to identify potential subtypes of hepatocellular carcinoma (HCC) associated with cirrhosis and to investigate key markers using bioinformatic analysis of gene expression datasets-0.
METHODS
Three data sets (GSE17548, GSE56140, and GSE87630) were extracted from the Gene Expression Omnibus (GEO) database and normalized using the Limma package in R. Principal component analysis (PCA) and cluster analysis was performed to examine data distribution and identify subtypes. Differential gene expression analysis was performed using the Limma software package. Protein-protein interaction analysis and functional annotation were performed using the STRING database and Cytoscape software. Important signaling pathways and processes were identified using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Analysis.
RESULTS
The analysis revealed different subtypes of HCC associated with cirrhosis and identified several key genes, including CCNB2, MCM4, and CDC20, with strong binding power and prognostic value. Functional annotation indicated involvement in cell cycle regulation and metabolic pathways. ROC analysis showed high sensitivity and specificity of these genes in predicting HCC prognosis.
CONCLUSION
These results suggest that CCNB2, MCM4, and CDC20 may serve as potential biomarkers for predicting HCC prognosis in patients with cirrhosis and provide insights into the molecular mechanisms of HCC progression.
PubMed: 38806996
DOI: 10.1007/s12094-024-03517-1 -
MedRxiv : the Preprint Server For... May 2024SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organ systems. Current hypotheses on mechanisms underlying long COVID...
SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organ systems. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and dysregulated coagulation; however, precise mechanisms and causal mediators remain unclear. Here, we tested the associations of genetic instruments for 49 complement and coagulation factors from the ( =34,557) with long COVID in the ( =997,600). Primary analyses revealed that genetically predicted higher factor XI increased long COVID risk (odds ratio, 1.17 [95% confidence interval, 1.08-1.27] per standard deviation; =1.7×10 ). This association was robust to sensitivity analyses using pleiotropy-robust methods and different genetic instruments and was replicated using proteogenomic data from an Icelandic cohort. Genetically predicted factor XI was also associated with venous thromboembolism, but not with acute COVID-19 or long COVID-resembling conditions. Collectively, these findings provide genetic evidence implicating factor XI in the biology of long COVID.
PubMed: 38798608
DOI: 10.1101/2024.05.17.24307553 -
Current Issues in Molecular Biology May 2024Proteogenomics represents a transformative intersection in nephrology, uniting genomics, transcriptomics, and proteomics to unravel the molecular intricacies of kidney... (Review)
Review
Proteogenomics represents a transformative intersection in nephrology, uniting genomics, transcriptomics, and proteomics to unravel the molecular intricacies of kidney diseases. This review encapsulates the methodological essence of proteogenomics and its profound implications in chronic kidney disease (CKD) research. We explore the proteogenomic pipeline, highlighting the integrated analysis of genomic, transcriptomic, and proteomic data and its pivotal role in enhancing our understanding of kidney pathologies. Through case studies, we showcase the application of proteogenomics in clear cell renal cell carcinoma (ccRCC) and Autosomal Recessive Polycystic Kidney Disease (ARPKD), emphasizing its potential in personalized treatment strategies and biomarker discovery. The review also addresses the challenges in proteogenomic analysis, including data integration complexities and bioinformatics limitations, and proposes solutions for advancing the field. Ultimately, this review underscores the prospective future of proteogenomics in nephrology, particularly in advancing personalized medicine and providing novel therapeutic insights.
PubMed: 38785547
DOI: 10.3390/cimb46050279 -
Molecular Cancer Therapeutics May 2024Endocrine therapies (ET) with CDK4/6 inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In...
Endocrine therapies (ET) with CDK4/6 inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of 22 ER+ breast cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.
PubMed: 38781103
DOI: 10.1158/1535-7163.MCT-23-0564 -
Frontiers in Cellular and Infection... 2024() belongs to the class , characterized by a very small genome size, reduction of metabolic pathways, including transcription factors, and the absence of a cell wall....
INTRODUCTION
() belongs to the class , characterized by a very small genome size, reduction of metabolic pathways, including transcription factors, and the absence of a cell wall. Despite this, they adapt well not only to specific niches within the host organism but can also spread throughout the body, colonizing various organs and tissues. The adaptation mechanisms of , as well as their regulatory pathways, are poorly understood. It is known that, when adapting to adverse conditions, can undergo phenotypic switches that may persist for several generations.
METHODS
To investigate the adaptive properties of related to survival in the host, we conducted a comparative phenotypic and proteogenomic analysis of eight clinical isolates of obtained from patients with urogenital infections and the laboratory strain H-34.
RESULTS
We have shown that clinical isolates differ in phenotypic features from the laboratory strain, form biofilms more effectively and show resistance to ofloxacin. The comparative proteogenomic analysis revealed that, unlike the laboratory strain, the clinical isolates possess several features related to stress survival: they switch carbon metabolism, activating the energetically least advantageous pathway of nucleoside utilization, which allows slowing down cellular processes and transitioning to a starvation state; they reconfigure the repertoire of membrane proteins; they have integrative conjugative elements in their genomes, which are key mediators of horizontal gene transfer. The upregulation of the methylating subunit of the restriction-modification (RM) system type I and the additional components of RM systems found in clinical isolates suggest that DNA methylation may play a role in regulating the adaptation mechanisms of in the host organism. It has been shown that based on the proteogenomic profile, namely the genome sequence, protein content, composition of the RM systems and additional subunits HsdM, HsdS and HsdR, composition and number of transposable elements, as well as the sequence of the main variable antigen Vaa, we can divide clinical isolates into two phenotypes: typical colonies (TC), which have a high growth rate, and atypical (aTC) mini-colonies, which have a slow growth rate and exhibit properties similar to persisters.
DISCUSSION
We believe that the key mechanism of adaptation of in the host is phenotypic restructuring, leading to a slowing down cellular processes and the formation of small atypical colonies. This is due to a switch in carbon metabolism and activation the pathway of nucleoside utilization. We hypothesize that DNA methylation may play a role in regulating this switch.
Topics: Humans; Mycoplasma hominis; Proteogenomics; Mycoplasma Infections; Adaptation, Physiological; Biofilms; Genome, Bacterial; Phenotype; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial
PubMed: 38756231
DOI: 10.3389/fcimb.2024.1398706