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Hematology (Amsterdam, Netherlands) Dec 2023Multiple myeloma (MM) is a malignant disease characterized by a single clonal proliferation of B cell-derived plasma cells in the bone marrow. It is the second most...
OBJECTIVES
Multiple myeloma (MM) is a malignant disease characterized by a single clonal proliferation of B cell-derived plasma cells in the bone marrow. It is the second most common haematologic malignancy in adults. The objective of this retrospective study is to evaluate the diagnostic and prognostic value of haematologic parameters in MM.
METHODS
The difference of NLR/ALB ratio (NAR) and NLR/HDL-C ratio (NHR) between the 151 newly diagnosed MM patients and 153 healthy controls was compared. According to NAR and NHR cutoff values obtained from the ROC curve, MM patients were divided into low group and high group. The differences in hematological parameters and survival time between the two groups were compared. Independent prognostic analysis was performed using Cox proportional hazard regression model.
RESULTS
The NAR and NHR values in MM group were significantly higher than those in control group ( < 0.001). Higher NAR levels were significantly associated with lower albumin (ALB), higher β2 microglobulin(β2-MG), higher creatinine (Crea), and highe ISS stage (All ). High NHR group was significantly correlated with age , β2-MG and ISS stage (All ). In high NAR or NHR groups, OS and DFS was significantly shortened and the prognosis was poor ( < 0.05). Multivariate analysis showed that PLT, ISS stage and NAR were independent prognostic indicators of OS in MM patients, while ALB, PLT and NAR were independent prognostic factors of DFS.
CONCLUSION
NAR and NHR are inexpensive, readily available diagnostic indicators for MM, and NAR is an independent prognostic factor for MM.
Topics: Adult; Humans; Prognosis; Multiple Myeloma; Retrospective Studies; Bone Marrow; Plasma Cells; Neutrophils
PubMed: 37493399
DOI: 10.1080/16078454.2023.2240145 -
American Journal of Clinical Pathology Jul 2023Plasma cell-rich rejection (PCCR), also known as "plasma cell hepatitis" or "de novo autoimmune hepatitis," is a cause of allograft dysfunction occurring post-liver...
OBJECTIVES
Plasma cell-rich rejection (PCCR), also known as "plasma cell hepatitis" or "de novo autoimmune hepatitis," is a cause of allograft dysfunction occurring post-liver transplantation (LT). Patients often develop allograft failure and may require repeat LT. PCRR may fall within the spectrum of different histologies associated with antibody-mediated rejection (AMR), which is associated with donor-specific antibodies (DSAs) and positive complement component C4 (C4d) immunostaining. We sought to analyze the histologic and clinical outcomes of patients having biopsy-proven PCRR as well as to examine its C4d staining and DSA profiles.
METHODS
We identified patients having PCRR between 2000 and 2020 using the electronic pathology database at our institution. We included patients who underwent at least one follow-up liver biopsy after establishing the PCRR diagnosis to assess future histologic progression and outcomes. Mean fluorescence intensity for at least one single DSA of 2,000 or higher was considered positive. Histologic diagnosis of PCRR was independently made by an experienced liver pathologist.
RESULTS
A total of 35 patients were included in the study. Hepatitis C virus was the most common etiology for LT (59.5%). Mean ± SD age at LT was 49.0 ± 12.7 years. Forty percent of patients developed PCRR within 2 years of LT. Most patients (68.5%) had negative outcomes, with progression from PCRR to cirrhosis or chronic ductopenic rejection (CDR). Patients who had hepatitis C virus were more likely to develop cirrhosis rather than CDR following the PCRR diagnosis (P = .01). Twenty-three (65.7%) patients had at least one prior episode of T-cell-mediated rejection before being diagnosed with PCRR. DSAs were positive in 16 of 19 patients assessed, and C4d immunostaining was positive in 9 of 10 patients.
CONCLUSIONS
Development of PCRR negatively affects liver allograft outcomes and patient survival after LT. The presence of DSA and C4d in PCRR patients supports it to be within the histologic spectrum of AMR.
Topics: Humans; Adult; Middle Aged; Liver Transplantation; Plasma Cells; Isoantibodies; Graft Rejection; Complement C4b; Liver Diseases; Liver Cirrhosis; Fibrosis; Biopsy; Peptide Fragments
PubMed: 36883807
DOI: 10.1093/ajcp/aqad004 -
Computers in Biology and Medicine Aug 2023Plasma cell leukemia (PCL) is one of the rare cancer which is characterized by the uncontrolled proliferation of plasma cells in peripheral blood and bone marrow. The...
BACKGROUND
Plasma cell leukemia (PCL) is one of the rare cancer which is characterized by the uncontrolled proliferation of plasma cells in peripheral blood and bone marrow. The aggressive behavior of the disease and high mortality rate among PCL patients makes it a thirst area to be explored.
METHODS
The dataset for PCL was obtained from the GEO database and was analyzed using GEO2R for differentially expressed genes. Further, the functional enrichment analysis was carried out for DEGs using DAVID. The protein-protein interactions (PPI) for DEGs were obtained using STRING 11.5 and were analyzed in Cytoscape 3.7.2. to obtain the key hub genes. These key hub genes were investigated for their interaction with suitable drug candidates using DGIdb, DrugMAP, and Schrodinger's version 2022-1.
RESULTS
Out of the total of 104 DEGs, 39 genes were up-regulated whereas 65 genes were down-regulated. A total of 11 biological processes, 2 cellular components, and 5 molecular functions were enriched along with the 7 KEGG pathways for the DEGs. Further, a total of 11 hub genes were obtained from the PPI of DEGs of which TP53, MAPK1, SOCS1, MBD3, and YES1 were the key hub genes. Oxaliplatin, mitoxantrone, and ponatinib were found to have the highest binding affinity towards the p53, MAPK1, and YES1 proteins respectively.
CONCLUSION
TP53, MAPK1, SOCS1, MBD3, and YES1 are the signature hub genes that might be responsible for the aggressive prognosis of PCL leading to poor survival rate. However, p53, MAPK1, and YES1 can be targeted with oxaliplatin, mitoxantrone, and ponatinib.
Topics: Humans; Gene Expression Profiling; Tumor Suppressor Protein p53; Oxaliplatin; Mitoxantrone; Leukemia, Plasma Cell; Computational Biology; Gene Expression Regulation, Neoplastic
PubMed: 37295388
DOI: 10.1016/j.compbiomed.2023.107090 -
The Journal of Allergy and Clinical... Feb 2024Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of...
BACKGROUND
Chronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody-secreting cells (ASCs), including plasma cells and plasmablasts, in their polyp tissue; in addition, their nasal polyp (NP) IgE levels are correlated with disease severity and recurrence of nasal polyposis.
OBJECTIVE
We sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of NP ASCs from patients with AERD and CRSwNP.
METHODS
NP tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. NP cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with or without IL-5 and analyzed by bulk RNA sequencing.
RESULTS
Compared with polyp tissue from patients with CRSwNP, polyp tissue from patients with AERD contained significantly more ASCs and had increased ASC expression of IL-5Rα. ASCs from patients with AERD expressed higher protein levels of B-cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. ASCs from patients with AERD also expressed more IL5RA, IGHE, and cell cycle- and proliferation-related transcripts (CCND2, MKI67, CDC25A, and CDC25B) than did ASCs from patients with CRSwNP. Stimulation of plasma cells from patients with AERD with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from patients with CRSwNP induced few transcriptomic changes.
CONCLUSION
NP tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation than do ASCs from patients with aspirin-tolerant CRSwNP.
Topics: Humans; Nasal Polyps; Interleukin-5; Rhinitis; Asthma, Aspirin-Induced; Aspirin; Chronic Disease; Antibody-Producing Cells; Sinusitis; Cell Proliferation; Neoplasm Proteins; Protein Tyrosine Phosphatases
PubMed: 37898408
DOI: 10.1016/j.jaci.2023.10.011 -
Journal of Crohn's & Colitis Feb 2024Creeping fat [CF] is a poorly understood feature of Crohn's disease [CD], characterized by the wrapping of mesenteric adipose tissue [MAT] around the inflamed intestine....
BACKGROUND AND AIMS
Creeping fat [CF] is a poorly understood feature of Crohn's disease [CD], characterized by the wrapping of mesenteric adipose tissue [MAT] around the inflamed intestine. The aim of this study was to investigate the transcriptional profile and compositional features of CF.
METHODS
We collected 59 MAT samples: 23 paired samples from patients with CD (CF [CD-CF] and MAT around the uninflamed intestine [CD-MAT]) and 13 MAT samples from non-CD patients [Con-MAT]. Differentially expressed gene [DEG], functional pathway, cell deconvolution, and gene co-expression network analyses were performed.
RESULTS
By comparing three different MAT samples, we identified a total of 529 DEGs [|log2FoldChange| > 1.5; false discovery rate < 0.05]. Of these, 323 genes showed an incremental pattern from Con-MAT to CD-MAT, and to CD-CF, while 105 genes displayed a decremental pattern. Genes with an incremental pattern were related to immune cell responses, including B- and T-cell activation, while genes with a decremental pattern were involved in cell trafficking and migration. Cell deconvolution analysis revealed significant changes in cellular composition between the CD-CF and Con-MAT groups, with increased proportions of B-cells/plasma cells [p = 1.16 × 10-4], T-cells [p = 3.66 × 10-3], and mononuclear phagocytes [p = 3.53 × 10-2] in the CD-CF group. In contrast, only the B-cell/plasma cell component showed a significant increase [p = 1.62 × 10-2] in the CD-MAT group compared to Con-MAT.
CONCLUSION
The distinct transcriptional profiles and altered cellular components of each MAT found in our study provide insight into the mechanisms behind CF and highlight its possible role in the pathogenesis of CD.
Topics: Humans; Crohn Disease; Intestines; Adipose Tissue; T-Lymphocytes; Gene Expression Profiling
PubMed: 37594364
DOI: 10.1093/ecco-jcc/jjad141 -
Human Pathology Sep 2023Stromal tumor-infiltrating lymphocytes (sTILs) are a robust prognostic and predictive biomarker in triple-negative breast carcinoma. However, the sTIL compartment...
Stromal tumor-infiltrating lymphocytes (sTILs) are a robust prognostic and predictive biomarker in triple-negative breast carcinoma. However, the sTIL compartment comprises different cell populations. The aim of the study is to characterize the distribution of T cells (CD3+ and CD8+), B cells, and plasma cells and explore their association with outcome in the surgical specimen of 62 patients. Furthermore, programmed death ligand 1 expression and the presence of tertiary lymphoid structures (TLSs) are explored. Patients with higher sTILs achieve better progression-free survival (PFS) (P = .0013), and tumors have more plasma cells in the infiltrate. Specifically, higher counts of T cells (both CD3+ and CD8+) have better PFS (P = .002 and P = .0086, respectively) as it is observed in tumors with higher infiltration of CD8+ T cells in the tumor core (P = .035). Higher infiltration by B cells and plasma cells shows a positive tendency toward increased PFS (P = .06 and P = .058). Programmed death ligand 1 (SP142) is positive in 56% of tumors. Tumors with at least 1 TLS (42%) show higher CD8+ T cell infiltration in the tumor core and the sTIL value doubles compared to tumors devoid of TLSs [sTIL mean: 36 ± 11% and 18 ± 5% (CI [Confidence Interval]: 95%), respectively]. Our study demonstrates that the characterization of the immune cell infiltration is as relevant as its distribution. Moreover, the importance of considering different immune cell types for classification is emphasized. Therefore, a new classification of triple-negative breast carcinoma immune infiltration with CD8+ T cell and plasma cell densities in the tumor core and infiltrative margin is proposed.
Topics: Humans; Plasma Cells; Triple Negative Breast Neoplasms; CD8-Positive T-Lymphocytes; Prognosis; Lymphocytes, Tumor-Infiltrating; B7-H1 Antigen; Tumor Microenvironment
PubMed: 37517596
DOI: 10.1016/j.humpath.2023.07.010 -
Journal of Clinical Immunology Oct 2023The human CD19 antigen is expressed throughout B cell ontogeny with the exception of neoplastic plasma cells and a subset of normal plasma cells. CD19 plays a role in...
BACKGROUND
The human CD19 antigen is expressed throughout B cell ontogeny with the exception of neoplastic plasma cells and a subset of normal plasma cells. CD19 plays a role in propagating signals from the B cell receptor and other receptors such as CXCR4 in mature B cells. Studies of CD19-deficient patients have confirmed its function during the initial stages of B cell activation and the production of memory B cells; however, its role in the later stages of B cell differentiation is unclear.
OBJECTIVE
Using B cells from a newly identified CD19-deficient individual, we investigated the role of CD19 in the generation and function of plasma cells using an in vitro differentiation model.
METHODS
Flow cytometry and long-read nanopore sequencing using locus-specific long-range amplification products were used to screen a patient with suspected primary immunodeficiency. Purified B cells from the patient and healthy controls were activated with CD40L, IL-21, IL-2, and anti-Ig, then transferred to different cytokine conditions to induce plasma cell differentiation. Subsequently, the cells were stimulated with CXCL12 to induce signalling through CXCR4. Phosphorylation of key downstream proteins including ERK and AKT was assessed by Western blotting. RNA-seq was also performed on in vitro differentiating cells.
RESULTS
Long-read nanopore sequencing identified the homozygous pathogenic mutation c.622del (p.Ser208Profs*19) which was corroborated by the lack of CD19 cell surface staining. CD19-deficient B cells that are predominantly naïve generate phenotypically normal plasma cells with expected patterns of differentiation-associated genes and normal levels of CXCR4. Differentiated CD19-deficient cells were capable of responding to CXCL12; however, plasma cells derived from naïve B cells, both CD19-deficient and sufficient, had relatively diminished signaling compared to those generated from total B cells. Additionally, CD19 ligation on normal plasma cells results in AKT phosphorylation.
CONCLUSION
CD19 is not required for generation of antibody-secreting cells or the responses of these populations to CXCL12, but may alter the response other ligands that require CD19 potentially affecting localization, proliferation, or survival. The observed hypogammaglobulinemia in CD19-deficient individuals is therefore likely attributable to the lack of memory B cells.
Topics: Humans; Plasma Cells; Antigens, CD19; Proto-Oncogene Proteins c-akt; B-Lymphocytes; Receptors, Antigen, B-Cell; Adaptor Proteins, Signal Transducing; Chemokine CXCL12
PubMed: 37246174
DOI: 10.1007/s10875-023-01511-w -
Research Square Sep 2023Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of...
Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Using a model antigen, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response. Clonal tracing using scRNA-seq+BCR-seq in spleen and bone marrow compartments, coupled with adoptive transfer experiments, reveal a novel PC transition state that gives rise to functionally competent PC precursors. The latter undergo clonal expansion, dependent on inducible expression of TIGIT. We propose a model for the proliferation and programming of precursors of long-lived PCs, based on extended antigen encounters followed by reduced antigen availability.
PubMed: 37720050
DOI: 10.21203/rs.3.rs-3296446/v1 -
BMJ Open Respiratory Research Dec 2023The heterogeneity of lung adenocarcinoma (LUAD) plays a vital role in determining the development of cancer and therapeutic sensitivity and significantly hinders the...
BACKGROUND
The heterogeneity of lung adenocarcinoma (LUAD) plays a vital role in determining the development of cancer and therapeutic sensitivity and significantly hinders the clinical treatment of LUAD.
OBJECTIVE
To elucidate the cellular composition and reveal previously uncharacterised tumour microenvironment in LUAD using single-cell RNA-sequencing (scRNA-seq).
METHODS
Two scRNA-seq datasets with 106 829 high-quality cells from 34 patients including 11 normal, 9 early (stage I and II) and 14 advanced (stage III and IV) LUAD were integrated and clustered to explore diagnostic and therapeutic cell populations and their biomarkers for diverse stages of LUAD. Three independent bulk RNA-seq datasets were used to validate the results from scRNA-seq analysis. The expression of marker genes for specific cell types in early and advanced LUAD was verified by immunohistochemistry (IHC).
RESULTS
Comprehensive cluster analysis identified that S100P+ epithelial and SPP1+ macrophage, positively related to poor outcomes, were preferentially enriched in advanced stage. Although the accumulation of KLRB1+CD8+ T cell and IGHA1+/IGHG1+ plasma cell both significantly associated the favourable prognosis, we also found KLRB1+CD8+ T cell decreased in advanced stage while IGHA1+/IGHG1+ plasma cells were increased. Cell-cell communication analysis showed that SPP1+ macrophage could interact with most of CD8+ subclusters through SPP1-CD44 axis. Furthermore, based on three independent bulk RNA-seq datasets, we built risk model with nine marker genes for specific cell subtypes and conducted deconvolution analysis, both supporting our results from scRNA-seq data. We finally validated the expression of four marker genes in early and advanced LUAD by IHC.
CONCLUSION
Our analyses highlight the molecular dynamics of LUAD epithelial and microenvironment and provide new targets to improve LUAD therapy.
Topics: Humans; Tumor Microenvironment; Adenocarcinoma of Lung; Cluster Analysis; Lung Neoplasms; RNA
PubMed: 38081768
DOI: 10.1136/bmjresp-2023-001878 -
Nephrology, Dialysis, Transplantation :... Nov 2023
Topics: Humans; Rituximab; Glomerulonephritis, Membranous; Plasma Cells; Autoantibodies; Receptors, Phospholipase A2
PubMed: 37401153
DOI: 10.1093/ndt/gfad135