Plasma Cells Research Articles

Spontaneous regression of multiple solitary plasmacytoma harboring Epstein-Barr virus: a case report and literature review.

We report a rare case of spontaneous regression (SR) in an elderly untreated patient with multiple solitary plasmacytoma (MSP). Diagnosis of MSP was confirmed through surgical resection of the left nasal cavity mass and subsequent biopsy of the right humerus. The patient was considered ineligible for chemotherapy due to poor performance status. At 3-month post-diagnosis, the patient's condition worsened with deteriorating bone lesions and emergence of a new serum monoclonal protein. However, these clinical findings completely disappeared at 6months, and positron emission tomography-computed tomography at 1year confirmed complete metabolic remission. Notably, peripheral blood lymphocyte counts were inversely correlated with tumor progression and remission. Pathological re-evaluation of the initial biopsy specimens revealed programmed cell death protein 1 (PD-1) expression in tumor-infiltrating CD8+ T cells. In addition, tumor cells were infected with Epstein-Barr virus (EBV) but were negative for programmed cell death ligand 1 (PD-L1) expression, which is the most potent immune escape mechanism in tumor cells. While the mechanism underlying SR remains unclear, our findings suggest that host immune response as well as EBV infection may contribute to SR. Further studies are needed to elucidate the clinicopathologic mechanisms of tumor regression in plasma cell neoplasms.

The Morphology of Nasal Polyps in Different Age Groups: Histopathological Features

Background: Nasal polyps (NPs) represent the end-stage manifestation of chronic rhinosinusitis (CRS), a relatively common pathological condition encountered in all ages of life. Methodology: The aim of our study was to evaluate the histological features and inflammatory cellular components of NPs in a retrospective cohort (143 cases) of pediatric, adult and elderly populations in order to discuss the possible morphological age-related differences statistically documented. Results: In the pediatric group, the inflammatory infiltrate presented many eosinophils mixed with lymphocytes, while in the adult population, lymphocytes and plasma cells were mainly evident, frequently with a perivascular distribution or with the formation of subepithelial lymphoid nodules. In the elderly population, inflammation was less evident and was associated with cavernous-like angecthatic structures with thrombotic stratification. Nearly all morphological findings exhibited statistically significant values among differently aged subgroups. Conclusions: Our results support the presence of histological specificities of NPs at different ages of life, providing new insight into the etiopathogenesis of NPs. The future role of biological therapies, mainly in cases refractory to already available standard medical and surgical treatments, may be analyzed by a prospective study using a larger cohort with a long-term evaluation also in relation to a possible relapse.

Prospective Association of Psychological Distress and Sexual Quality of Life Among Hematopoietic Stem Cell Transplant Survivors.

Sexual health concerns are one of the most common late effects facing hematopoietic stem cell transplant (HSCT) survivors. The current study tested whether self-reported depression and anxiety symptoms before transplant were associated with embedded items assessing two specific areas of sexual health-sexual interest and sexual satisfaction-one year post-HSCT. Of the 158 study participants, 41% were diagnosed with a plasma cell disorder (n = 60) and most received autologous transplantation (n = 128; 81%). At post-HSCT, 21% of participants reported they were not at all satisfied with their sex life, and 22% were not at all interested in sex. Greater pre-HSCT depressive symptomology was significantly predictive of lower sexual interest (β = -.27, p < .001) and satisfaction (β = -.39, p < .001) at post-HSCT. Similarly, greater pre-HSCT trait anxiety was significantly predictive of lower sexual interest (β = -.19, p = .02) whereas higher levels of state and trait anxiety were both predictive of lower satisfaction (β = -.22, p = .02 and β = -.29, p = .001, respectively). Participant sex significantly moderated the relationship between state anxiety and sexual satisfaction (b = -.05, t = -2.03, p = .04). Additional research examining the factors that contribute to sexual health post-HCST is needed to inform and implement clinical interventions to address these commonly overlooked survivorship concerns.

Synergistic action of synthetic peptides and amphotericin B causes disruption of the plasma membrane and cell wall in Candida albicans.

The objective of this work was to evaluate the combination of synthetic peptides based on the γ-core motif of defensin PvD1 with amphotericin B (AmB) at different concentrations against Candida albicans. We applied the checkerboard assay using different concentrations of the commercial drug AmB and the synthetic peptides γ31-45PvD1++ and γ33-41PvD1++ against C. albicans, aiming to find combinations with synergistic interactions. Between these two interactions involving γ31-45PvD1++ and AmB, an additive effect was observed. One such interaction occurred at concentrations of 0.009 µM of peptide γ31-45PvD1++ and 13.23 µM of AmB and another condition of 0.019 µM of peptide γ31-45PvD1++ and 6.61 µM of AmB. The other two concentrations of the interaction showed a synergistic effect in the combination of synthetic peptide γ31-45PvD1++ and AmB, where the concentrations were 1.40 µM peptide γ31-45PvD1++ and 0.004 µM AmB and 0.70 µM γ31-45PvD1++ peptide and 0.002 µM AmB. We proceeded with analysis of the mechanism of action involving synergistic effects. This examination unveiled a range of impactful outcomes, including the impairment of mitochondrial functionality, compromise of cell wall integrity, DNA degradation, and a consequential decline in cell viability. We also observed that both synergistic combinations were capable of causing damage to the plasma membrane and cell wall, causing leakage of intracellular components. This discovery demonstrates for the first time that the synergistic combinations found between the synthetic peptide γ31-45PvD1++ and AmB have an antifungal effect against C. albicans, acting on the integrity of the plasma membrane and cell wall.

The role of cGAMP via the STING pathway in modulating germinal center responses and CD4 T cell differentiation

Germinal center (GC) responses are essential for establishing protective, long-lasting immunity through the differentiation of GC B cells (BGC) and plasma cells (BPC), along with the generation of antigen-specific antibodies. Among the various pathways influencing immune responses, the STING (Stimulator of Interferon Genes) pathway has emerged as significant, especially in innate immunity, and extends its influence to adaptive responses. In this study, we examined how the STING ligand cGAMP can modulate these key elements of the adaptive immune response, particularly in enhancing GC reactions and the differentiation of BGC, BPC, and follicular helper T cells (TFH). Employing in vivo models, we evaluated various antigens and the administration of cGAMP in Alum adjuvant, investigating the differentiation of BGC, BPC, and TFH cells, along with the production of antigen-specific antibodies. cGAMP enhances the differentiation of BGC and BPC, leading to increased antigen-specific antibody production. This effect is shown to be type I Interferon-dependent, with a substantial reduction in BPC frequency upon interferon (IFN)-β blockade. Additionally, cGAMP’s influence on TFH differentiation varies over time, which may be critical for refining vaccine strategies. The findings elucidate a complex, antigen-specific influence of cGAMP on T and B cell responses, providing insights that could optimize vaccine efficacy.

IgM kappa proliferative glomerulonephritis with monoclonal immunoglobulin deposition complicated with nocardiosis dermatitis: a case report and review of literature

RationaleMonoclonal gammopathy of renal significance (MGRS) represents a group of disorders caused by monoclonal immunoglobulin (M protein) secreted by B cells or plasma cells. Proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID) is a glomerular disease and a form of MGRS. Here, we presented a rare case of a patient with IgM kappa PGNMID complicated with nocardiosis dermatitis.Patient concerns and diagnosesA 56-year-old man was admitted to the hospital because of cutaneous purpura and proteinuria. His initial pathological diagnosis indicated membranous proliferative glomerulonephritis, IgM(++), and subacute interstitial nephritis. Based on further examination, he was finally diagnosed to have IgM kappa PGNMID and subacute interstitial nephritis. After the initial diagnosis, the patient received hormonal therapy. During the treatment, nocardiosis dermatitis emerged as a complication, and the hormonal therapy was gradually reduced. The patient refused further treatment with rituximab, and his health is currently stable.OutcomesIgM kappa PGNMID complicated with nocardiosis dermatitis is an extremely rare occurrence. Laboratory examination and pathological analysis are required to confirm the diagnosis of this disorder. Timely and accurate diagnosis is essential for the appropriate treatment of PGNMID.

Integrin αvβ3 Limits Cytokine Production by Plasmacytoid Dendritic Cells and Restricts TLR-Driven Autoimmunity.

Plasmacytoid dendritic cells (pDCs) are strongly implicated as a major source of IFN-I in systemic lupus erythematosus (SLE), triggered through TLR-mediated recognition of nucleic acids released from dying cells. However, relatively little is known about how TLR signaling and IFN-I production are regulated in pDCs. In this article, we describe a role for integrin αvβ3 in regulating TLR responses and IFN-I production by pDCs in mouse models. We show that αv and β3-knockout pDCs produce more IFN-I and inflammatory cytokines than controls when stimulated through TLR7 and TLR9 invitro and invivo. Increased cytokine production was associated with delayed acidification of endosomes containing TLR ligands, reduced LC3 conjugation, and increased TLR signaling. This dysregulated TLR signaling results in activation of B cells and promotes germinal center (GC) B cell and plasma cell expansion. Furthermore, in a mouse model of TLR7-driven lupus-like disease, deletion of αvβ3 from pDCs causes accelerated autoantibody production and pathology. We therefore identify a pDC-intrinsic role for αvβ3 in regulating TLR signaling and preventing activation of autoreactive B cells. Because αvβ3 serves as a receptor for apoptotic cells and cell debris, we hypothesize that this regulatory mechanism provides important contextual cues to pDCs and functions to limit responses to self-derived nucleic acids.

Hormones and B-cell development in health and autoimmunity

The development of B cells into antibody-secreting plasma cells is central to the adaptive immune system as they induce protective and specific antibody responses against invading pathogens. Various studies have shown that, during this process, hormones can play important roles in the lymphopoiesis, activation, proliferation, and differentiation of B cells, and depending on the signal given by the receptor of each hormone, they can have a positive or negative effect. In autoimmune diseases, hormonal deregulation has been reported to be related to the survival, activation and/or differentiation of autoreactive clones of B cells, thus promoting the development of autoimmunity. Clinical manifestations of autoimmune diseases have been associated with estrogens, prolactin (PRL), and growth hormone (GH) levels. However, androgens, such as testosterone and progesterone (P4), could have a protective effect. The objective of this review is to highlight the links between different hormones and the immune response mediated by B cells in the etiopathogenesis of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). The data collected provide insights into the role of hormones in the cellular, molecular and/or epigenetic mechanisms that modulate the B-cell response in health and disease.

Accelerated plasma-cell differentiation in Bach2-deficient mouse B cells is caused by altered IRF4 functions.

Transcription factors BACH2 and IRF4 are both essential for antibody class-switch recombination (CSR) in activated B lymphocytes, while they oppositely regulate the differentiation of plasma cells (PCs). Here, we investigated how BACH2 and IRF4 interact during CSR and plasma-cell differentiation. We found that BACH2 organizes heterochromatin formation of target gene loci in mouse splenic B cells, including targets of IRF4 activation such as Aicda, an inducer of CSR, and Prdm1, a master plasma-cell regulator. Release of these gene loci from heterochromatin in response to B-cell receptor stimulation was coupled to AKT-mTOR pathway activation. In Bach2-deficient B cells, PC genes' activation depended on IRF4 protein accumulation, without an increase in Irf4 mRNA. Mechanistically, a PU.1-IRF4 heterodimer in activated B cells promoted BACH2 function by inducing gene expression of Bach2 and Pten, a negative regulator of AKT signaling. Elevated AKT activity in Bach2-deficient B cells resulted in IRF4 protein accumulation. Thus, BACH2 and IRF4 mutually modulate the activity of each other, and BACH2 inhibits PC differentiation by both the repression of PC genes and the restriction of IRF4 protein accumulation.

Bispecific antibodies for the treatment of relapsed/refractory multiple myeloma: updates and future perspectives

Patients with relapsed/refractory multiple myeloma (RRMM) that are refractory to the five most active anti-MM drugs, so-called penta-refractory MM, have historically had dismal outcomes with subsequent therapies. Progressive immune dysfunction, particularly of the T-cell repertoire, is implicated in the development of disease progression and refractory disease. However, the advent of novel immunotherapies such as bispecific antibodies are rapidly changing the treatment landscape and improving the survival outcomes of patients with RRMM. Bispecific antibodies are antibodies that are engineered to simultaneously engage cytotoxic immune effector cells (T cells or NK cells) and malignant plasma cells via binding to immune effector cell antigens and extracellular plasma cell antigens leading to immune effector cell activation and malignant plasma cell destruction. Currently, bispecific antibodies that bind CD3 on T cells and plasma cell epitopes such as B-cell maturation antigen (BCMA), G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5) are the most advanced in clinical development and are showing unprecedented response rates in patients with RRMM, including patients with penta-refractory disease. In this review article, we explore the available clinical data of bispecific antibodies in RRMM and summarize the efficacy, safety, toxicity, clinical outcomes, mechanisms of resistance, and future directions of these therapies in patients with RRMM.

Circulating plasma cells as a predictive biomarker in Multiple myeloma: an updated systematic review and meta-analysis

Background Circulating plasma cells (CPCs) are defined by the presence of peripheral blood clonal plasma cells, which would contribute to the progression and dissemination of multiple myeloma (MM). An increasing number of studies have demonstrated the predictive potential of CPCs in the past few years. Therefore, there is a growing need for an updated meta-analysis to identify the specific relationship between CPCs and the prognosis of MM based on the current research status. Methods The PubMed, Embase, and Cochrane Library databases were screened to determine eligible studies from inception to November 5, 2023. Publications that reported the prognostic value of CPCs in MM patients were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and progression-free survival (PFS) were extracted to pool the results. Subgroup analyses were performed based on region, sample size, cut-off value, detection time, initial treatment, and data type. The association between CPCs level and clinicopathological characteristics, including the International Staging System (ISS), Revised-ISS (R-ISS), and cytogenetic abnormalities were also evaluated. Statistical analyses were conducted using STATA 17.0 software. Results Twenty-two studies with a total of 5637 myeloma patients were enrolled in the current meta-analysis. The results indicated that myeloma patients with elevated CPCs were expected to have a poor OS (HR = 2.19, 95% CI: 1.81–2.66, p < 0.001) and PFS (HR = 2.45, 95% CI: 1.93–3.12, p < 0.001). Subgroup analyses did not alter the prognostic role of CPCs, regardless of region, sample size, cut-off value, detection time, initial treatment, or data type. Moreover, the increased CPCs were significantly related to advanced tumour stage (ISS III vs. ISS I–II: pooled OR = 2.89, 95% CI: 2.41–3.46, p < 0.001; R-ISS III vs. R-ISS I–II: pooled OR = 3.65, 95% CI: 2.43–5.50, p < 0.001) and high-risk cytogenetics (high-risk vs. standard-risk: OR = 2.22, 95% CI: 1.60–3.08, p < 0.001). Conclusion Our meta-analysis confirmed that the increased number of CPCs had a negative impact on the PFS and OS of MM patients. Therefore, CPCs could be a promising prognostic biomarker that helps with risk stratification and disease monitoring.

Modelling Myeloma Dissemination in vitro with hMSC-Interacting Subpopulations of INA-6 Cells and their Aggregation/Detachment Dynamics.

Multiple myeloma involves early dissemination of malignant plasma cells across the bone marrow; however, the initial steps of dissemination remain unclear. Human bone marrow-derived mesenchymal stromal cells (hMSCs) stimulate myeloma cell expansion (e.g., IL-6) and simultaneously retain myeloma cells via chemokines (e.g., CXCL12) and adhesion factors. Hence, we hypothesized that the imbalance between cell division and retention drives dissemination. We present an in vitro model using primary hMSCs co-cultured with INA-6 myeloma cells. Time-lapse microscopy revealed proliferation and attachment/detachment dynamics. Separation techniques (V-well adhesion assay and well plate sandwich centrifugation) were established to isolate MSC-interacting myeloma subpopulations that were characterized by RNAseq, cell viability and apoptosis. Results were correlated with gene expression data (n=837) and survival of myeloma patients (n=536). On dispersed hMSCs, INA-6 saturate hMSC-surface before proliferating into large homotypic aggregates, from which single cells detached completely. On confluent hMSCs, aggregates were replaced by strong heterotypic hMSC-INA-6 interactions, which modulated apoptosis time-dependently. Only INA-6 daughter cells (nMA-INA6) detached from hMSCs by cell division but sustained adherence to hMSC-adhering mother cells (MA-INA6). Isolated nMA-INA6 indicated hMSC-autonomy through superior viability after IL-6 withdrawal and upregulation of proliferation-related genes. MA-INA6 upregulated adhesion and retention factors (CXCL12), that, intriguingly, were highly expressed in myeloma samples from patients with longer overall and progression-free survival, but their expression decreased in relapsed myeloma samples. Altogether, in vitro dissemination of INA-6 is driven by detaching daughter cells after a cycle of hMSC-(re)attachment and proliferation, involving adhesion factors that represent a bone marrow-retentive phenotype with potential clinical relevance.

Colonization during a key developmental window reveals microbiota-dependent shifts in growth and immunity during undernutrition

BackgroundChildhood undernutrition is a major global health challenge with devastating lifelong consequences. Linear growth stunting due to undernutrition has been linked to poor health outcomes, and mothers who experience growth stunting in childhood are more likely to give birth to stunted children later in life. Based on these findings, we hypothesized that intergenerational colonization of mice with microbiota from human donors with undernutrition may recapitulate certain immune and growth changes observed in this disorder.ResultsTo test this hypothesis, we developed a gnotobiotic murine model of undernutrition using microbiota from human infants with healthy or stunted growth trajectories. Intergenerational colonization with microbiota derived from children with growth stunting lead to less linear growth and the development of immune features of undernutrition and enteropathy, including intestinal villus blunting, lower liver IGF-1 and accumulation of intraepithelial lymphocytes and plasma cells in the small intestine. In contrast, colonization after weaning lead to fewer host phenotypic changes between these distinct microbial communities.ConclusionsThese results are broadly consistent with previous findings demonstrating that exposure of the immune system to microbial products during the weaning phase is a critical determinant of later life immune function. Overall, our results suggest intergenerational colonization with human microbiota samples is a useful approach with which to investigate microbiota-dependent changes in growth and immunity in early life. Murine models that capture the intergenerational and multifactorial nature of undernutrition are critical to understanding the underlying biology of this disorder.7T5ZN13mtZ1d8dLkaKDJxvVideo

Targeted therapy for multiple myeloma: an overview on CD138-based strategies

Multiple myeloma (MM) is an incurable hematological disease characterized by the uncontrolled growth of plasma cells primarily in the bone marrow. Although its treatment consists of the administration of combined therapy regimens mainly based on immunomodulators and proteosome inhibitors, MM remains incurable, and most patients suffer from relapsed/refractory disease with poor prognosis and survival. The robust results achieved by immunotherapy targeting MM-associated antigens CD38 and CD319 (also known as SLAMF7) have drawn attention to the development of new immune-based strategies and different innovative compounds in the treatment of MM, including new monoclonal antibodies, antibody-drug conjugates, recombinant proteins, synthetic peptides, and adaptive cellular therapies. In this context, Syndecan1 (CD138 or SDC1), a transmembrane heparan sulfate proteoglycan that is upregulated in malignant plasma cells, has gained increasing attention in the panorama of MM target antigens, since its key role in MM tumorigenesis, progression and aggressiveness has been largely reported. Here, our aim is to provide an overview of the most important aspects of MM disease and to investigate the molecular functions of CD138 in physiologic and malignant cell states. In addition, we will shed light on the CD138-based therapeutic approaches currently being tested in preclinical and/or clinical phases in MM and discuss their properties, mechanisms of action and clinical applications.

Long-lived Plasma Cells Associated with Replapsing Anti-NMDAR Encephalitis (P6-14.002)

Long-lived Plasma Cells Associated with Replapsing Anti-NMDAR Encephalitis (P6-14.002)

Successful Treatment of Posttransplant Monoclonal Gammopathy-associated C3 Glomerulopathy With Plasma Cell Clone-directed Therapy.

Successful Treatment of Posttransplant Monoclonal Gammopathy-associated C3 Glomerulopathy With Plasma Cell Clone-directed Therapy.

The choice of serum‐free light chain analysis method could potentially have clinical consequences for myeloma patients

AbstractMultiple myeloma (MM) is a disease, that at times poses diagnostic and monitoring challenges. Over the last decades laboratory methods have been expanded with serum free light chain (FLC) analysis. Alerted by two index cases with clinical impact due to failure of the FLC analysis to indicate a disease progression, we aimed to identify any clinical consequences due to known differences between FLC analysis methods. We applied two FLC analysis methods (Freelite Binding Site [FBS] and N‐Latex Siemens [NLS]) on all patients with MM and monoclonal gammopathy of uncertain significance diagnosed/followed up at Södra Älvsborg Hematology Unit, from April to December 2022. From a total of 123 patients with malignant plasma cell disorder, we identified five cases (4.1%) where solely the FBS method, as opposed to NLS, urine and serum electrophoresis, could support diagnosis or detect progression. The consequences of this discrepancy included not only change of diagnosis or delayed therapy but also change of treatment. Our findings indicate that a stronger awareness of the potential weaknesses of different FLC methods is needed, which calls for a closer collaboration between clinical chemists and hematologists.

Transcriptomic analysis reveals molecular characterization and immune landscape of PANoptosis-related genes in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease characterized by abnormal lipid deposition in the arteries. Programmed cell death is involved in the inflammatory response of atherosclerosis, but PANoptosis, as a new form of programmed cell death, is still unclear in atherosclerosis. This study explored the key PANoptosis-related genes involved in atherosclerosis and their potential mechanisms through bioinformatics analysis. We evaluated differentially expressed genes (DEGs) and immune infiltration landscape in atherosclerosis using microarray datasets and bioinformatics analysis. By intersecting PANoptosis-related genes from the GeneCards database with DEGs, we obtained a set of PANoptosis-related genes in atherosclerosis (PANoDEGs). Functional enrichment analysis of PANoDEGs was performed and protein-protein interaction (PPI) network of PANoDEGs was established. The machine learning algorithms were used to identify the key PANoDEGs closely linked to atherosclerosis. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic potency of key PANoDEGs. CIBERSORT was used to analyze the immune infiltration patterns in atherosclerosis, and the Spearman method was used to study the relationship between key PANoDEGs and immune infiltration abundance. The single gene enrichment analysis of key PANoDEGs was investigated by GSEA. The transcription factors and target miRNAs of key PANoDEGs were predicted by Cytoscape and online database, respectively. The expression of key PANoDEGs was validated through animal and cell experiments. PANoDEGs in atherosclerosis were significantly enriched in apoptotic process, pyroptosis, necroptosis, cytosolic DNA-sensing pathway, NOD-like receptor signaling pathway, lipid and atherosclerosis. Four key PANoDEGs (ZBP1, SNHG6, DNM1L, and AIM2) were found to be closely related to atherosclerosis. The ROC curve analysis demonstrated that the key PANoDEGs had a strong diagnostic potential in distinguishing atherosclerotic samples from control samples. Immune cell infiltration analysis revealed that the proportion of initial B cells, plasma cells, CD4 memory resting T cells, and M1 macrophages was significantly higher in atherosclerotic tissues compared to normal tissues. Spearman analysis showed that key PANoDEGs showed strong correlations with immune cells such as T cells, macrophages, plasma cells, and mast cells. The regulatory networks of the four key PANoDEGs were established. The expression of key PANoDEGs was verified in further cell and animal experiments. This study evaluated the expression changes of PANoptosis-related genes in atherosclerosis, providing a reference direction for the study of PANoptosis in atherosclerosis and offering potential new avenues for further understanding the pathogenesis and treatment strategies of atherosclerosis.

The role of hsa_circ_0042260/miR-4782-3p/LAPTM4A axis in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a common metabolic condition during pregnancy, posing risks to both mother and fetus. CircRNAs have emerged as important players in various diseases, including GDM. We aimed to investigate the role of newly discovered circRNA, hsa_circ_0042260, in GDM pathogenesis. Using GSE194119 dataset, hsa_circ_0042260 was identified and its expression in plasma, placenta, and HG-stimulated HK-2 cells was examined. Silencing hsa_circ_0042260 in HK-2 cells assessed its impact on cell viability, apoptosis, and inflammation. Bioinformatics analysis revealed downstream targets of hsa_circ_0042260, namely miR-4782-3p and LAPTM4A. The interaction between hsa_circ_0042260, miR-4782-3p, and LAPTM4A was validated through various assays. hsa_circ_0042260 was upregulated in plasma from GDM patients and HG-stimulated HK-2 cells. Silencing hsa_circ_0042260 improved cell viability, suppressed apoptosis and inflammation. Hsa_circ_0042260 interacted with miR-4782-3p, which exhibited low expression in GDM patient plasma and HG-stimulated cells. MiR-4782-3p targeted LAPTM4A, confirmed by additional assays. LAPTM4A expression increased in GDM patient plasma and HG-induced HK-2 cells following hsa_circ_0042260 knockdown or miR-4782-3p overexpression. In rescue assays, inhibition of miR-4782-3p or overexpression of LAPTM4A counteracted the effects of hsa_circ_0042260 downregulation on cell viability, apoptosis, and inflammation. In conclusion, the hsa_circ_0042260/miR-4782-3p/LAPTM4A axis plays a role in regulating GDM progression in HG-stimulated HK-2 cells.

[Clinicopathological characteristics and immune microenvironment of breast squamous cell carcinoma].

Objective: To investigate the clinicopathological characteristics of breast squamous cell carcinoma and to analyze the relationship between its immune microenvironment tumor infiltrating lymphocytes (TILs) and prognosis. Methods: Forty-four cases of primary squamous cell carcinoma of the breast diagnosed and treated in the First Affiliated Hospital of Air Force Medical University, Xi'an, China from January 2006 to July 2022 were selected. Their clinicopathological characteristics were analyzed. The cell composition of TILs was evaluated using immunohistochemistry (Mainly markers of B lymphocytes, T lymphocytes and plasma cells). The relationship between TILs and prognosis was also analyzed. Results: The 44 patients of breast squamous cell carcinoma were all female and all were invasive carcinoma. Eight cases (8/44, 18.2%) were squamous cell carcinoma, while 36 cases (36/44, 81.8%) were mixed squamous cell carcinoma. The mixed components included non-specific carcinoma and spindle cell metaplastic carcinoma (17 cases each). One case contained ductal carcinoma in situ of the breast and 1 case contained tubular carcinoma. The proportion of squamous cell carcinoma was 10% to 90%. The cases with pure squamous cell carcinoma often had a large cystic cavity, which was lined by atypical squamous epithelium, while infiltrating squamous cell carcinoma nests were seen in the breast tissue around the cystic cavity. Immunohistochemical staining showed that p63 and CK5/6 were expressed in the squamous cell carcinoma component, but ER, PR and HER2 were not, except for one case of HER2 1+. The positive rates of TRPS1 and PDL-1 were 76% and less than 1%, respectively. Fifteen cases were in the high TILs group (TILs≥30%) and 29 cases were in the low TILs group (TILs<30%). Twenty-three patients were followed up for 5 to 118 months. Among them, 12 died within 3 years and 9 were alive at the end of the follow up. There was no significant difference in TNM stage, TILs and prognosis between simple squamous cell carcinoma and mixed squamous cell carcinoma. Conclusions: Breast squamous cell carcinoma can be divided into simple squamous cell carcinoma and mixed squamous cell carcinoma. There are differences in gross findings and histology between the simple and mixed squamous cell carcinoma of the breast. Sufficient samples should be taken to avoid missing the diagnosis of a minor squamous component. The prognosis of patients with high TILs is significantly better than that of patients with low TILs. The expression rate of TRPS1 in primary squamous cell carcinoma of breast is high and helpful to the differential diagnosis from metastatic squamous cell carcinoma.