EBV-Positive Pleomorphic Variant Transformation of CD5-Negative Mantle Cell Lymphoma: A Rare Case Report and Literature Review.

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma associated with cyclin D family rearrangements and typically expresses CD5 and cyclin D1. Epstein-Barr virus- (EBV-) positive MCL is rare, and the role of EBV infection and its transformation in MCL remains unclear. We present a case of CD5-negative classic MCL that progressed to an EBV + pleomorphic MCL six years after the initial diagnosis. Molecular studies confirmed the same clonal origin. To the best of our knowledge, the EBV-positive transformation of CD5-negative MCL into a pleomorphic variant has rarely been reported, and its recognition is important for the diagnosis and the management of patients with MCL.

The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases.

Interleukin-6 (IL-6) is a pleiotropic cytokine and exerts its complex biological functions mainly through three different signal modes, called cis-, trans-, and cluster signaling. When IL-6 binds to its membrane or soluble receptors, the co-receptor gp130 is activated to initiate downstream signaling and induce the expression of target genes. In the liver, IL-6 can perform its anti-inflammatory activities to promote hepatocyte reprogramming and liver regeneration. On the contrary, IL-6 also exerts the pro-inflammatory functions to induce liver aging, fibrosis, steatosis, and carcinogenesis. However, understanding the roles and underlying mechanisms of IL-6 in liver physiological and pathological processes is still an ongoing process. So far, therapeutic agents against IL­6, IL­6 receptor (IL­6R), IL-6-sIL-6R complex, or IL-6 downstream signal transducers have been developed, and determined to be effective in the intervention of inflammatory diseases and cancers. In this review, we summarized and highlighted the understanding of the double-edged effects of IL-6 in liver homeostasis, aging, inflammation, and chronic diseases, for better shifting the "negative" functions of IL-6 to the "beneficial" actions, and further discussed the potential therapeutic effects of targeting IL-6 signaling in the clinics.

AHNAK2 Regulates NF-κB/MMP-9 Signaling to Promote Pancreatic Cancer Progression.

Early metastasis of pancreatic cancer (PaC) is a major cause of its high mortality rate. Previous studies have shown that AHNAK2 is involved in the progression of some tumors and is predicted to be an independent prognostic factor for PaC; however, the specific mechanisms through which AHNAK2 regulates PaC remain unclear. In this study, we examined the role of AHNAK2 in PaC and its potential molecular mechanisms. AHNAK2 mRNA and protein expression in PaC tissues and cells were measured using qRT-PCR and western blot analysis. After AHNAK2 knockdown using small interfering RNA, PaC cells were subjected to CCK-8 scratch, and Transwell assays to assess cell proliferation, migration, and invasion, respectively. Furthermore, the validation of the mechanistic pathway was achieved by western blot analysis. AHNAK2 mRNA and protein levels were up-regulated in PaC and silencing AHNAK2 significantly inhibited the proliferation, migration, and invasion of PaC cells. Mechanistically, AHNAK2 knockdown decreased the expression of phosphorylated p65, phosphorylated IκBα, and matrix metalloproteinase-9 (MMP-9), suggesting that activation of the NF-κB/MMP-9 signaling pathway was inhibited. Importantly, activation of NF-κB reversed the effects of AHNAK2 knockdown. Our findings indicate that AHNAK2 promotes PaC progression through the NF-kB/MMP-9 pathway and provides a theoretical basis for targeting AHNAK2 for the treatment of PaC.

Ferroptosis contributes to airway epithelial E-cadherin disruption in a mixed granulocytic asthma mouse model.

Aberrant expression of airway epithelial E-cadherin is a key feature of asthma, yet the underlying mechanisms are largely unknown. Ferroptosis is a novel form of regulated cell death involved in asthma pathogenesis. This study was aimed to evaluate the role of ferroptosis and to investigate whether ferroptosis mediates E-cadherin disruption in mixed granulocyte asthma (MGA). Two murine models of MGA were established using toluene diisocyanate (TDI) or ovalbumin with Complete Freund's Adjuvant (OVA/CFA). Specific antagonists of ferroptosis, including Liproxstatin-1 (Lip-1) and Ferrostatin-1 (Fer-1) were given to the mice. The allergen-exposed mice displayed markedly shrunk mitochondria in the airway epithelia, with decreased volume and denser staining accompanied by down-regulated GPX4 as well as up-regulated FTH1 and malondialdehyde, which are markers of ferroptosis. Decreased pulmonary expression of E-cadherin was also observed, with profound loss of membrane E-cadherin in the airway epithelia, as well as increased secretion of sE-cadherin. Treatment with Lip-1 not only showed potent protective effects against the allergen-induced airway hyperresponsiveness and inflammatory responses, but also rescued airway epithelial E-cadherin expression and inhibited the release of sE-cadherin. Taken together, our data demonstrated that ferroptosis mediates airway epithelial E-cadherin dysfunction in MGA.

Exploring natural killer cell-related biomarkers in multiple myeloma: a novel nature killer cell-related model predicting prognosis and immunotherapy response using single-cell study.

BACKGROUND: Natural killer cells (NKs) may be involved in multiple myeloma (MM) progression. The present study elucidated the correlation between NKs and the progression of MM using single-cell binding transcriptome probes to identify NK cell-related biomarkers. METHODS: Single-cell analysis was performed including cell and subtype annotation, cell communication, and pseudotime analysis. Hallmark pathway enrichment analysis of NKs and NKs-related differentially expressed genes (DEGs) were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction (PPI) networks. Then, a risk model was structured based on biomarkers identified through univariate Cox regression analysis and least absolute shrinkage and selection operator regression analysis and subsequently validated. Additionally, correlation of clinical characteristics, gene set enrichment analysis, immune analysis, regulatory network, and drug forecasting were explored. RESULTS: A total of 13 cell clusters were obtained and annotated, including 8 cell populations that consisted of NKs. Utilizing 123 PPI network node genes, 8 NK-related DEGs were selected to construct a prognostic model. Immune cell infiltration results suggested that 11 immune cells exhibited marked differences in the high and low-risk groups. Finally, the model was used to screen potential drug targets to enhance immunotherapy efficacy. CONCLUSION: A new prognostic model for MM associated with NKs was constructed and validated. This model provides a fresh perspective for predicting patient outcomes, immunotherapeutic response, and candidate drugs.

Cost-effectiveness comparison of dalpiciclib and abemaciclib combined with an aromatase inhibitor as first-line treatment for HR+/HER2- advanced breast cancer.

OBJECTIVES: CDK4/6 inhibitors dalpiciclib and abemaciclib have been approved by the Chinese National Medical Products Administration as first-line treatment for postmenopausal females with hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC). We aimed to assess the cost-effectiveness of dalpiciclib plus letrozole/anastrozole (non-steroidal aromatase inhibitor [NSAI]) compared with abemaciclib plus NSAI as a first-line treatment for HR+/HER2- ABC in China. METHODS: We constructed a Markov model with three health states to evaluate health and economic outcomes of first-line treatment with dalpiciclib plus NSAI and abemaciclib plus NSAI for HR+/HER2- ABC. Efficacy data was obtained from MONARCH3 and DAWNA-2 trials. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: Compared with abemaciclib plus NSAI, dalpiciclib plus NSAI resulted in 4.27 additional QALYs, with an ICER of $14827.4/QALY. At a willingness-to-pay threshold of 3 times gross domestic product per capita in China for 2023 ($37721.5/QALY), the cost-effectiveness probability of dalpiciclib plus NSAI was 77.42%. CONCLUSIONS: From the perspective of Chinese payers, dalpiciclib plus NSAI appears to be a cost-effective strategy compared with abemaciclib plus NSAI for the first-line treatment of patients with HR+/HER2- ABC in China. CLINICAL TRIAL REGISTRATION: MONARCH3, www.clinicaltrials.gov, identifier is NCT02246621 and DAWNA-2, www.clinicaltrials.gov, identifier is NCT03966898.

GLUT1 regulates the release of VEGF-A in the alveolar epithelium of lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) is a severe disease with high mortality and poor prognosis, characterized by excessive and uncontrolled inflammatory response. Vascular endothelial growth factor A (VEGF-A) contributes to the development and progression of ALI. The aim of this study was to evaluate the role of glucose transporter 1 (GLUT1) in alveolar epithelial VEGF-A production in lipopolysaccharide (LPS)-induced ALI. An ALI mouse model was induced by LPS oropharyngeal instillation. Mice were challenged with LPS and then treated with WZB117, a specific antagonist of GLUT1. For the vitro experiments, cultured A549 cells (airway epithelial cell line) were exposed to LPS, with or without the GLUT1 inhibitors WZB117 or BAY876. LPS significantly upregulated of GLUT1 and VEGF-A both in the lung from ALI mice and in cultured A549. In vivo, treatment with WZB117 not only markedly decreased LPS-induced pulmonary edema, injury, neutrophilia, as well as levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF), but also reduced VEGF-A production. Yet, the maximum tolerated concentration of WZB117 failed to suppress LPS-induced VEGF-A overexpression in vitro. While administration of BAY876 inhibited gene and protein expression as well as secretion of VEGF-A in response to LPS in A549. These results illustrated that GLUT1 upregulates VEGF-A production in alveolar epithelia from LPS-induced ALI, and inhibition of GLUT1 alleviates ALI.

A second-generation M1-polarized CAR macrophage with antitumor efficacy.

Chimeric antigen receptor (CAR) T cell therapies have successfully treated hematological malignancies. Macrophages have also gained attention as an immunotherapy owing to their immunomodulatory capacity and ability to infiltrate solid tumors and phagocytize tumor cells. The first-generation CD3ζ-based CAR-macrophages could phagocytose tumor cells in an antigen-dependent manner. Here we engineered induced pluripotent stem cell-derived macrophages (iMACs) with toll-like receptor 4 intracellular toll/IL-1R (TIR) domain-containing CARs resulting in a markedly enhanced antitumor effect over first-generation CAR-macrophages. Moreover, the design of a tandem CD3ζ-TIR dual signaling CAR endows iMACs with both target engulfment capacity and antigen-dependent M1 polarization and M2 resistance in a nuclear factor kappa B (NF-κB)-dependent manner, as well as the capacity to modulate the tumor microenvironment. We also outline a mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we provide a second-generation CAR-iMAC with an ability for orthogonal phagocytosis and polarization and superior antitumor functions in treating solid tumors relative to first-generation CAR-macrophages.

Review and Updates on Systemic Mastocytosis and Related Entities.

Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical outcomes. Mastocytosis is the pathologic process of the accumulation of abnormal mast cells in different organs, mostly driven by KIT mutations, and can present as cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma. The WHO 5th edition classification divides systemic mastocytosis into bone marrow mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. The new ICC classifies SM slightly differently. The diagnosis of SM requires the integration of bone marrow morphologic, immunophenotypic, and molecular findings, as well as clinical signs and symptoms. Moreover, understanding the wide range of clinical presentations for patients with mast cell disorders is necessary for accurate and timely diagnosis. This review provides an updated overview of mast cell disorders, with a special emphasis on SM, including the latest approaches to diagnosis, prognostic stratification, and management of this rare disease.

Uncovering the transcriptional responses of tobacco (Nicotiana tabacum L.) roots to Ralstonia solanacearum infection: a comparative study of resistant and susceptible cultivars.

BACKGROUND: Tobacco bacterial wilt (TBW) caused by Ralstonia solanacearum is the most serious soil-borne disease of tobacco that significantly reduces crop yield. However, the limited availability of resistance in tobacco hinders breeding efforts for this disease. RESULTS: In this study, we conducted hydroponic experiments for the root expression profiles of D101 (resistant) and Honghuadajinyuan (susceptible) cultivars in response to BW infection at 0 h, 6 h, 1 d, 3 d, and 7d to explore the defense mechanisms of BW resistance in tobacco. As a result, 20,711 and 16,663 (total: 23,568) differentially expressed genes (DEGs) were identified in the resistant and susceptible cultivars, respectively. In brief, at 6 h, 1 d, 3 d, and 7 d, the resistant cultivar showed upregulation of 1553, 1124, 2583, and 7512 genes, while the susceptible cultivar showed downregulation of 1213, 1295, 813, and 7735 genes. Similarly, across these time points, the resistant cultivar had downregulation of 1034, 749, 1686, and 11,086 genes, whereas the susceptible cultivar had upregulation of 1953, 1790, 2334, and 6380 genes. The resistant cultivar had more up-regulated genes at 3 d and 7 d than the susceptible cultivar, indicating that the resistant cultivar has a more robust defense response against the pathogen. The GO and KEGG enrichment analysis showed that these genes are involved in responses to oxidative stress, plant-pathogen interactions, cell walls, glutathione and phenylalanine metabolism, and plant hormone signal transduction. Among the DEGs, 239 potential candidate genes were detected, including 49 phenylpropane/flavonoids pathway-associated, 45 glutathione metabolic pathway-associated, 47 WRKY, 48 ERFs, eight ARFs, 26 pathogenesis-related genes (PRs), and 14 short-chain dehydrogenase/reductase genes. In addition, two highly expressed novel genes (MSTRG.61386-R1B-17 and MSTRG.61568) encoding nucleotide-binding site leucine-rich repeat (NBS-LRR) proteins were identified in both cultivars at 7 d. CONCLUSIONS: This study revealed significant enrichment of DEGs in GO and KEGG terms linked to glutathione, flavonoids, and phenylpropane pathways, indicating the potential role of glutathione and flavonoids in early BW resistance in tobacco roots. These findings offer fundamental insight for further exploration of the genetic architecture and molecular mechanisms of BW resistance in tobacco and solanaceous plants at the molecular level.

Exosome-delivered circRNA circSYT15 contributes to cisplatin resistance in cervical cancer cells through the miR-503-5p/RSF1 axis.

The development of chemotherapy resistance is a major obstacle for cervical cancer (CC) patients. Exosome-mediated transfer of circular RNAs (circRNAs) was found to have relevance to the CC. This study is designed to explore the role and mechanism of exosomal circRNA synaptotagmin 15 (circSYT15) on cisplatin (DDP) resistance in CC. Cell proliferation ability and apoptosis rate were detected by Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), colony formation, and flow cytometry assays. CircSYT15, microRNA-503-5p (miR-503-5p), Remodeling spacing factor 1 (RSF1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Exosomes were analyzed by a transmission electron microscope and nanoparticle tracking analysis. CD63, CD81, TSC101, Bcl-2, Bax, C-caspase 3, and RSF1 protein levels were examined by western blot assay. The binding between miR-503-5p and circSYT15 or RSF1 was predicted by circBank or Starbase and then verified by a dual-luciferase reporter and RNA Immunoprecipitation (RIP). The biological role of exosomal circSYT15 in DDP resistance of CC in vivo. CircSYT15 was upregulated in the DDP-resistant CC cells and exosomes isolated from DDP-resistant CC cells. CircSYT15 knockdown repressed the proliferation and drug resistance of CC and induced apoptosis in CC cells. Exosomes shuttled circSYT15 act as a sponge to affect RSF1 expression, thereby promoting proliferation and drug resistance and repressing apoptosis of sensitive CC cells. Exosomal circSYT15 boost DDP resistance of cervical cancer in vivo. Exosome-mediated transfer of circSYT15 enhanced DDP resistance in CC partly by targeting the miR-503-5p/RSF1 axis, providing a foundation for future clinical applications of CC drug resistance.

N6-methyladenosine modification promotes hepatocarcinogenesis through circ-CDYL-enriched and EpCAM-positive liver tumor-initiating exosomes.

CircRNAs play multiple roles in a variety of cellular processes. We found that Circ-CDYL is highly enriched in early HCC plasma exosomes. Moreover, EpCAM+ HCC cells and exosomes had significant Circ-CDYL levels. We postulated that Circ-CDYL-enriched and EpCAM-positive exosomes would function as liver tumor-initiating exosomes (LTi-Exos). As predicted, intercellular transfer of LTi-Exos activates the HDGF-PI3K-AKT-mTOR and HIF1AN-NOTCH2 axes in recipient cells, promoting malignancy. Upstream, we found that the N6-methyladenosine (m6A) modification of Circ-CDYL exerted its action in HCC cells through a dual mechanism. First, it stimulated back-splicing processes via YTHDC1 to promote Circ-CDYL biogenesis. Second, it facilitates the active sorting of Circ-CDYL into exosomes via hnRNPA2/B1. Clinically, the combination of LTi-Exos and plasma alpha-fetoprotein (AFP) provides a promising early diagnostic biomarker for HCC with an AUC of 0.896. This study highlights the effect and mechanism by which m6A modification promotes hepatocarcinogenesis via modulation of the tumor microenvironment by LTi-Exos.

Roles of four targets in the pathogenesis of graves' orbitopathy.

Graves' orbitopathy (GO) is an autoimmune disease that involves complex immune systems. The mainstays of clinical management for this disease are surgery, targeted drugs therapy, and no-targeted drugs drug therapy. targeted drugs can improve therapeutic efficacy and enhance the quality of life for GO patients. However, as a second-line treatment for GO, targeted drugs such as tocilizumab and rituximab have very limited therapeutic effects and may be accompanied by side effects. The introduction of Teprotumumab, which targets IGF-IR, has made significant progress in the clinical management of GO. The pathophysiology of GO still remains uncertain as it involves a variety of immune cells and fibroblast interactions as well as immune responses to relevant disease targets of action. Therfore, learning more about immune response feedback pathways and potential targets of action will assist in the treatment of GO. In this discussion, we explore the pathogenesis of GO and relevant work, and highlight four potential targets for GO: Interleukin-23 receptor (IL-23 R), Leptin receptor (LepR), Orbital fibroblast activating factors, and Plasminogen activator inhibitor-1 (PAI-1). A deeper understanding of the pathogenesis of GO and the role of potential target signaling pathways is crucial for effective treatment of this disease.

The latest edition of WHO and ELN guidance and a new risk model for Chinese acute myeloid leukemia patients.

Objective: Diagnosis classification and risk stratification are crucial in the prognosis prediction and treatment selection of acute myeloid leukemia (AML). Here, we used a database of 536 AML patients to compare the 4th and 5th WHO classifications and the 2017 and 2022 versions of ELN guidance. Methods: AML patients were classified according to the 4th and 5th WHO classifications, as well as the 2017 and 2022 versions of the European LeukemiaNet (ELN) guidance. Kaplan-Meier curves with log-rank tests were used for survival analysis. Results: The biggest change was that 25 (5.2%), 8 (1.6%), and 1 (0.2%) patients in the AML, not otherwise specified (NOS) group according to the 4th WHO classification, were re-classified into the AML-MR (myelodysplasia-related), KMT2A rearrangement, and NUP98 rearrangement subgroups based on the 5th WHO classification. Referring to the ELN guidance, 16 patients in the favorable group, six patients in the adverse group, and 13 patients in the intermediate group based on the 2017 ELN guidance were re-classified to the intermediate and adverse groups based on the 2022 ELN guidance. Regrettably, the Kaplan-Meier curves showed that the survival of intermediate and adverse groups could not be distinguished well according to either the 2017 or 2022 ELN guidance. To this end, we constructed a risk model for Chinese AML patients, in which the clinical information (age and gender), gene mutations (NPM1, RUNX1, SH2B3, and TP53), and fusions (CBFB::MYH11 and RUNX1::RUNX1T1) were included, and our model could help divide the patients into favorable, intermediate, and adverse groups. Conclusion: These results affirmed the clinical value of both WHO and ELN, but a more suitable prognosis model should be established in Chinese cohorts, such as the models we proposed.

Microcystin-LR-Induced Interaction between M2 Tumor-Associated Macrophage and Colorectal Cancer Cell Promotes Colorectal Cancer Cell Migration through Regulating the Expression of TGF-ß1 and CST3.

Microcystin-LR (MC-LR) is a toxic secondary metabolite produced by cyanobacteria that has been demonstrated to promote colorectal cancer (CRC). However, the mechanism by which MC-LR enhances CRC in the tumor microenvironment (TME) is poorly understood. To elucidate its role in TME, a co-culture system was established using CRC cells and M2 macrophages in a Transwell chamber. The study found that MC-LR promotes CRC cell migration by upregulating TGF-ß1 expression and secretion in M2 macrophages and downregulating CST3 in CRC cells. Neutralizing TGF-ß1 increased CST3 expression in CRC cells, while overexpressing CST3 in CRC cells suppressed TGF-ß1 expression in M2 macrophages, both of which weakened MC-LR-induced cellular motility in the co-culture system. In vivo, the mice in the MC-LR/AOM/DSS group had more tumor nodules, deeper tumor invasion, and higher M2 macrophage infiltration compared to the AOM/DSS group, and the expression of TGF-ß1 and CST3 in tumors was consistent with the cellular level. Overall, this study provides insights into the regulatory mechanism of MC-LR on TME, revealing that MC-LR upregulates the expression and secretion of TGF-ß1 in M2 macrophages, which in turn inhibits the expression of CST3 in CRC cells to promote migration.

Combined assessment of health hazard and odour impact of soils at a contaminated site: a case study on a defunct pharmaceuticals factory in China.

Surveys and assessments of contaminated sites primarily focus on hazardous pollutants in the soil with less attention paid to odorants. This makes the management of contaminated sites difficult. In this study, hazardous and odorous pollutants in the soil were assessed for a large site that was previously used for production of pharmaceuticals to determine the degree and characteristics of soil contamination at pharmaceutical production sites, for undertaking rational remediation measures. The main hazardous pollutants at the study site were triethylamine, n-butyric acid, benzo(a)pyrene (BaP), N-nitrosodimethylamine (NDMA), dibenzo(a,h)anthracene (DBA), total petroleum hydrocarbons (C10-C40) (TPH), and 1,2-dichloroethane; TEA, BA, and isovaleric acid (IC) were the main odorants. As the type and distribution of hazardous and odorous pollutants differ, it is necessary to separately assess the impact of these pollutants at a contaminated site. Soils in the surface layer pose significant non-carcinogenic (HI = 68.30) and carcinogenic risks (RT = 3.56E-5), whereas those in the lower layer only pose non-carcinogenic risks (HI > 7.43). Odorants were found at considerable concentrations both in the surface and lower layers, with the maximum concentrations being 29,309.91 and 41.27, respectively. The findings of this study should improve our understanding of soil contamination at former pharmaceutical production sites and should inform the assessment of the risks posed by contaminated sites, with problems associated with odour, and possible remediation strategies.

Case report: Co-existing chronic myeloid leukemia and chronic myelomonocytic leukemia-A clinically important but challenging scenario.

Chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML) are two common myeloid neoplasms with overlapping morphologic features. We report a patient initially diagnosed with CML and treated with Tyrosine kinase inhibitor (TKI) but who then developed persistent monocytosis and worsening thrombocytopenia one year later. Repeat bone marrow biopsies only showed CML at the molecular level. However, markedly hypercellular bone marrow, megakaryocytic dysplasia, and SRSF2, TET2, and RUNX1 mutations by NextGen sequencing pointed to a diagnosis of CMML. For CML patients with persistent monocytosis and cytopenia, a mutational profile by NGS is helpful to exclude or identify the coexisting CMML.