-
Blood Jul 2024Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While...
Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.
PubMed: 38958467
DOI: 10.1182/blood.2023023727 -
Cancer Investigation Jul 2024Myeloproliferative neoplasms (MPN) are hematological diseases associated with genetic driver mutations in the JAK2, CALR, and MPL genes and exacerbated oncoinflammatory...
Myeloproliferative neoplasms (MPN) are hematological diseases associated with genetic driver mutations in the JAK2, CALR, and MPL genes and exacerbated oncoinflammatory . Analyzing public microarray data from polycythemia vera (n = 41), essential thrombocythemia (n = 21), and primary myelofibrosis (n = 9) patients' peripheral blood by approaches, we found that pro-inflammatory and monocyte-related genes were differentially expressed in MPN patients' transcriptome. Genes related to cell activation, secretion of pro-inflammatory and pro-angiogenic mediators, activation of neutrophils and platelets, coagulation, and interferon pathway were upregulated in monocytes compared to controls. Together, our results suggest that molecular alterations in monocytes may contribute to oncoinflammation in MPN.
PubMed: 38958254
DOI: 10.1080/07357907.2024.2371371 -
American Journal of Reproductive... Jul 2024This study aimed to evaluate the predictive value of delta neutrophil index (DNI), a peripheral blood parameter, on perinatal outcomes in pregnant women with systemic...
PROBLEM
This study aimed to evaluate the predictive value of delta neutrophil index (DNI), a peripheral blood parameter, on perinatal outcomes in pregnant women with systemic lupus erythematosus (SLE).
METHOD OF STUDY
One hundred eighty-one participants, 78 pregnant women with SLE, and 103 healthy pregnant women were included in this retrospective study. Peripheral blood parameters including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and DNI taken in the first trimester were compared between groups.
RESULTS
NLR, PLR, and DNI were significantly higher in the SLE group (p = 0.027, p = 0.007, p = 0.0001, respectively). The same parameters were not found to be significant in determining disease activity in pregnant women with SLE (p > 0.05). When the predictive value of DNI for SGA in pregnancies with SLE was evaluated by receiver operating characteristic curve (ROC), the area under the ROC curve (AUC) was 0.666 (95% CI; 0.544-0.788, p = 0.018) with 84.6% sensitivity, 53.8% specificity, 56.0% PPV, and 78.1% NPV at a cut-off value of 0.16. The predictive value of DNI according to ROC for stillbirth in pregnancies with SLE was AUC 0.731 (95% CI: 0.539-0.923, p = 0.019) with a cut-off value of 0.17, sensitivity of 90%, specificity of 51.5%, PPV of 58.5%, and NPV of 87.2%.
CONCLUSIONS
Although DNI's prediction of SGA and stillbirth in pregnant women with SLE is encouraging, it needs more evidence from prospective studies with larger series.
Topics: Humans; Female; Pregnancy; Lupus Erythematosus, Systemic; Neutrophils; Adult; Retrospective Studies; Pregnancy Complications; Pregnancy Outcome; Predictive Value of Tests; ROC Curve; Lymphocytes; Infant, Newborn
PubMed: 38958243
DOI: 10.1111/aji.13894 -
Clinical Chemistry Jul 2024Liquid biopsies are emerging as valuable clinical biomarkers for cancer monitoring. Although International Organization for Standards (ISO) and Technical Specifications...
BACKGROUND
Liquid biopsies are emerging as valuable clinical biomarkers for cancer monitoring. Although International Organization for Standards (ISO) and Technical Specifications from the European Committee for Standardization (CEN/TS) standardized workflows exist, their implementation in clinical practice is underdeveloped. We aimed to assess the applicability of ISO and CEN/TS standards in a real-world clinical setting, with a particular focus on evaluating the impact of preanalytical parameters and hemolysis on liquid biopsy analysis.
METHODS
We evaluated 659 peripheral blood samples from advanced prostate cancer patients against ISO and CEN/TS standards and documented all essential criteria, including tube draw order, filling level, temperature, and time tracking from blood draw to storage. We assessed hemolysis and its effect on circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) analysis.
RESULTS
Our results demonstrated a high compliance rate, with 96.2% (634/659) of samples meeting essential ISO and CEN/TS criteria. We did not observe a significant impact on ctDNA or CTC detection rates between hemolytic and nonhemolytic samples. Hemolysis was identified in 12.9% (40/311) of plasma samples from our advanced prostate cancer cohort, and within the draw order of 5 blood collection tubes, hemolysis did not significantly increase from tube 1 to 5. In total, 83.8% (552/659) of blood collection tubes had high fill levels above 80% of nominal filling level.
CONCLUSIONS
Our study demonstrates the feasibility and benefits of adhering to ISO and CEN/TS standards in a clinical liquid biopsy study. The standards revealed that hemolysis occurred frequently but did not impair downstream ctDNA and CTC analysis in our cohort of advanced prostate cancer patients.
PubMed: 38958115
DOI: 10.1093/clinchem/hvae079 -
Epigenomics Jul 2024We investigate the genome-wide DNA methylation (DNAm) patterns of term low birth weight (TLBW) neonates. In the discovery phase, we assayed 32 samples...
We investigate the genome-wide DNA methylation (DNAm) patterns of term low birth weight (TLBW) neonates. In the discovery phase, we assayed 32 samples (TLBW/control:16/16) using the EPIC 850k BeadChip Array. Targeted pyrosequencing of in 60 samples (TLBW/control:28/32) using targeted pyrosequencing during the replication phase. The 850K array identified TLBW-associated 144 differentially methylated positions (DMPs) and 149 DMRs. Nearly 77% DMPs exhibited hypomethylation, located in the opensea and gene body regions. The most significantly enriched pathway in KEGG is sphingolipid metabolism (hsa00600), and the genes and related to this pathway both show hypomethylation. Our analysis provides evidence of genome-wide DNAm alterations in TLBW. Further investigations are needed to elucidate the functional significance of these DNAm changes.
PubMed: 38957889
DOI: 10.1080/17501911.2024.2358744 -
Frontiers in Immunology 2024Chemoresistance constitutes a prevalent factor that significantly impacts thesurvival of patients undergoing treatment for smal-cell lung cancer (SCLC). Chemotherapy...
INTRODUCTION
Chemoresistance constitutes a prevalent factor that significantly impacts thesurvival of patients undergoing treatment for smal-cell lung cancer (SCLC). Chemotherapy resistance in SCLC patients is generally classified as primary or acquired resistance, each governedby distinct mechanisms that remain inadequately researched.
METHODS
In this study, we performed transcriptome screening of peripheral blood plasma obtainedfrom 17 patients before and after receiving combined etoposide and platinum treatment. We firs testimated pseudo-single-cell analysis using xCell and ESTIMATE and identified differentially expressed genes (DEGs), then performed network analysis to discover key hub genes involved in chemotherapy resistance.
RESULTS
Our analysis showed a significant increase in class-switched memory B cell scores acrossboth chemotherapy resistance patterns, indicating their potential crucial role in mediatingresistance. Moreover, network analysis identifed , , and as potential contributors to primary resistance, with , and emerging assignificant factors in acquired resistance, providing valuable insights into chemotherapy resistancein SCLC.
DISCUSSION
These findings offer valuable insights for understanding chemotherapy resistance and related gene signatures in SCLC, which could help further biological validation studies.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Drug Resistance, Neoplasm; Biomarkers, Tumor; Transcriptome; Female; Male; Gene Expression Profiling; Middle Aged; Gene Expression Regulation, Neoplastic; Aged; Antineoplastic Combined Chemotherapy Protocols; Etoposide
PubMed: 38957470
DOI: 10.3389/fimmu.2024.1338162 -
Frontiers in Immunology 2024There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To...
There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To explore the immune-driven ECM remodelling in COVID-19, we in this explorative study analysed these interactions in hospitalised COVID-19 patients. RNA sequencing and flow analysis were performed on peripheral blood mononuclear cells. Inflammatory mediators in plasma were measured by ELISA and MSD, and clinical information from hospitalised COVID-19 patients (N=15) at admission was included in the analysis. Further, we reanalysed two publicly available datasets: (1) lung tissue RNA-sequencing dataset (N=5) and (2) proteomics dataset from PBCM. ECM remodelling pathways were enriched in PBMC from COVID-19 patients compared to healthy controls. Patients treated at the intensive care unit (ICU) expressed distinct ECM remodelling gene profiles compared to patients in the hospital ward. Several markers were strongly correlated to immune cell subsets, and the dysregulation in the ICU patients was positively associated with plasma levels of inflammatory cytokines and negatively associated with B-cell activating factors. Finally, our analysis of publicly accessible datasets revealed (i) an augmented ECM remodelling signature in inflamed lung tissue compared to non-inflamed tissue and (ii) proteomics analysis of PBMC from severe COVID-19 patients demonstrated an up-regulation in an ECM remodelling pathway. Our results may suggest the presence of an interaction between ECM remodelling, inflammation, and immune cells, potentially initiating or perpetuating pulmonary pathology in severe COVID-19.
Topics: Humans; COVID-19; Leukocytes, Mononuclear; Extracellular Matrix; Male; Female; Middle Aged; SARS-CoV-2; Aged; Cytokines; Proteomics; Lung; Adult
PubMed: 38957465
DOI: 10.3389/fimmu.2024.1379570 -
Frontiers in Immunology 2024Probiotic consumption strongly influences local intestinal immunity and systemic immune status. strain SANK70258 (HC) is a spore-forming lactic acid bacterium that has... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
strain SANK70258 suppresses symptoms of upper respiratory tract infection via immune modulation: a randomized, double-blind, placebo-controlled, parallel-group, comparative study.
Probiotic consumption strongly influences local intestinal immunity and systemic immune status. strain SANK70258 (HC) is a spore-forming lactic acid bacterium that has immunostimulatory properties on peripheral tissues. However, few reports have examined the detailed effectiveness of HC on human immune function and its mechanism of action. Therefore, we conducted a randomized, double-blind, placebo-controlled, parallel-group study to comprehensively evaluate the effects of HC on immunostimulatory capacity, upper respiratory tract infection (URTI) symptoms, and changes in intestinal organic-acid composition. Results of a questionnaire survey of URTI symptoms showed that runny nose, nasal congestion, sneezing, and sore throat scores as well as the cumulative number of days of these symptoms were significantly lower in the HC group than in the placebo group during the study period. Furthermore, the salivary secretory immunoglobulin A (sIgA) concentration was significantly higher, and the natural killer (NK) cell activity tended to be higher in the HC group than in the placebo group. In addition, we performed an exposure culture assay of inactivated influenza virus on peripheral blood mononuclear cells (PBMCs) isolated from the blood of participants in the HC and placebo groups. Gene-expression analysis in PBMCs after culture completion showed that IFNα and TLR7 expression levels were significantly higher in the HC group than in the placebo group. In addition, the expression levels of CD304 tended to be higher in the HC group than in the placebo group. On the other hand, the HC group showed a significantly higher increase in the intestinal butyrate concentration than the placebo group. HC intake also significantly suppressed levels of IL-6 and TNFα produced by PBMCs after exposure to inactivated influenza virus. Collectively, these results suggest that HC activated plasmacytoid dendritic cells expressing TLR7 and CD304 and strongly induced IFNα production, subsequently activating NK cells and increasing sIgA levels, and induced anti-inflammatory effects via increased intestinal butyrate levels. These changes may contribute to the acquisition of host resistance to viral infection and URTI prevention.
Topics: Humans; Respiratory Tract Infections; Double-Blind Method; Male; Adult; Probiotics; Female; Young Adult; Leukocytes, Mononuclear; Killer Cells, Natural; Gastrointestinal Microbiome; Immunoglobulin A, Secretory; Toll-Like Receptor 7; Immunomodulation
PubMed: 38957464
DOI: 10.3389/fimmu.2024.1389920 -
Journal of Hepatocellular Carcinoma 2024Long noncoding RNAs (lncRNAs) might be closely associated with hepatocellular carcinoma (HCC) progression and could serve as diagnostic and prognostic markers. This...
The Potential of the lncRNAs ADAMTSL4-AS1, AC067931 and SOCS2-AS1 in Peripheral Blood Mononuclear Cells as Novel Diagnostic Biomarkers for Hepatitis B Virus-Associated Hepatocellular Carcinoma.
PURPOSE
Long noncoding RNAs (lncRNAs) might be closely associated with hepatocellular carcinoma (HCC) progression and could serve as diagnostic and prognostic markers. This study aimed to investigate lncRNA-based diagnostic biomarkers for hepatitis B virus (HBV)-associated HCC.
MATERIALS AND METHODS
High-throughput transcriptome sequencing was conducted on the liver tissues of 15 patients with HBV-associated liver diseases (5 with chronic hepatitis B [CHB], 5 with liver cirrhosis [LC], and 5 with HCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze lncRNA expressions. Potential diagnostic performance for HBV-associated HCC screening was evaluated.
RESULTS
Through trend analysis and functional analysis, we found that 8 lncRNAs were gradually upregulated and 1 lncRNA was progressively downregulated by regulation of target mRNAs and downstream HCC-associated signaling pathways. The validation of dysregulated lncRNAs in peripheral blood mononuclear cells (PBMCs) and HCC tissues by qRT-PCR revealed that ADAMTSL4-AS1, SOCS2-AS1, and AC067931 were significantly increased in HCC compared with CHB and cirrhosis. Moreover, differentially expressed lncRNAs were aberrantly elevated in Huh7, Hep3B, HepG2, and HepG2.215 cells compared with LX2 cells. Furthermore, ADAMTSL4-AS1, SOCS2-AS1, and AC067931 were identified as novel biomarkers for HBV-associated HCC. For distinguishing HCC from CHB, ADAMTSL4-AS1, AC067931, and SOCS2-AS1 combined with alpha-fetoprotein (AFP) had an area under the curve (AUC) of 0.945 (sensitivity, 83.9%; specificity, 89.8%). Similarly, for distinguishing HCC from LC, this combination had an AUC of 0.871 (sensitivity, 91.1%; specificity, 68.2%). Furthermore, this combination showed the highest diagnostic ability to distinguish HCC from CHB and LC (AUC, 0.905; sensitivity, 91.1%; specificity, 75.3%). In particular, this combination identified AFP-negative (AFP < 20 ng/mL) (AUC = 0.814), small (AUC = 0.909), and early stage (AUC = 0.863) tumors.
CONCLUSION
ADAMTSL4-AS1, SOCS2-AS1, and AC067931 combined with AFP in PBMCs may serve as a noninvasive diagnostic biomarker for HBV-associated HCC, especially AFP-negative, small, and early stage HCC.
PubMed: 38957436
DOI: 10.2147/JHC.S463804 -
Journal of Cellular and Molecular... Jul 2024This research explores the role of microRNA in senescence of human endothelial progenitor cells (EPCs) induced by replication. Hsa-miR-134-5p was found up-regulated in...
This research explores the role of microRNA in senescence of human endothelial progenitor cells (EPCs) induced by replication. Hsa-miR-134-5p was found up-regulated in senescent EPCs where overexpression improved angiogenic activity. Hsa-miR-134-5p, which targeted transforming growth factor β-activated kinase 1-binding protein 1 (TAB1) gene, down-regulated TAB1 protein, and inhibited phosphorylation of p38 mitogen-activated protein kinase (p38) in hsa-miR-134-5p-overexpressed senescent EPCs. Treatment with siRNA specific to TAB1 (TAB1si) down-regulated TAB1 protein and subsequently inhibited p38 activation in senescent EPCs. Treatment with TAB1si and p38 inhibitor, respectively, showed angiogenic improvement. In parallel, transforming growth factor Beta 1 (TGF-β1) was down-regulated in hsa-miR-134-5p-overexpressed senescent EPCs and addition of TGF-β1 suppressed the angiogenic improvement. Analysis of peripheral blood mononuclear cells (PBMCs) disclosed expression levels of hsa-miR-134-5p altered in adult life, reaching a peak before 65 years, and then falling in advanced age. Calculation of the Framingham risk score showed the score inversely correlates with the hsa-miR-134-5p expression level. In summary, hsa-miR-134-5p is involved in the regulation of senescence-related change of angiogenic activity via TAB1-p38 signalling and via TGF-β1 reduction. Hsa-miR-134-5p has a potential cellular rejuvenation effect in human senescent EPCs. Detection of human PBMC-derived hsa-miR-134-5p predicts cardiovascular risk.
Topics: MicroRNAs; Humans; Endothelial Progenitor Cells; Cellular Senescence; Leukocytes, Mononuclear; Middle Aged; Adaptor Proteins, Signal Transducing; Male; Cardiovascular Diseases; p38 Mitogen-Activated Protein Kinases; Female; Aged; Neovascularization, Physiologic; Transforming Growth Factor beta1; Adult; Risk Factors
PubMed: 38957039
DOI: 10.1111/jcmm.18523