Activation of Notch-1 signaling pathway in macrophages to secrete PD-L1 and regulate cytotoxicity of CAR-T cells in diffuse large B-cell lymphoma.

OBJECTIVE: To investigate the mechanism of action of the Notch-1/IRE1/XBP1s signaling pathway in diffuse large B-cell lymphoma (DLBCL). METHODS: The expressions of relevant proteins were detected by Western blotting. The effect of myeloid-specific knockout of Notch-1 on lymphoma progression was observed by mouse tumor transplantation and imaging. The apoptosis of chimeric antigen receptor T-cell therapy (CAR-T) cells were detected by flow cytometry, and the proliferation of CAR-T cells was detected by wound healing assay and cell counting kit-8 (CCK8) assay. RESULTS: Lymphoma cells mediated the Notch-1 signaling pathway in bone marrow-derived macrophages and promoted the activation of STAT3 and STAT6 in bone marrow-derived macrophages. Myeloid-specific knockout of Notch-1 could inhibit the progression of lymphoma. Lymphoma cells enhanced the expression of p-PERK, p-IRE1α, ATF6, IL-6, IL-4, p-AKT, CD9, CD63 and PD-L1 in bone marrow-derived macrophages by mediating the Notch-1 signaling pathway. Knockout of Notch-1 in macrophages alleviated, to some extent, the suppression of killing activity of CAR-T cells, while activation of Notch-1 in macrophages inhibited proliferation and promoted apoptosis of CAR-T cells. The PD-L1 antibody significantly restored the cytotoxicity and proliferation of CAR-T cells, and inhibited their apoptosis. CONCLUSION: Activation of the Notch-1/IRE1/XBP1s signaling pathway in myeloid macrophages promotes the secretion of IL-6 and IL-4 as well as PD-L1, thereby inhibiting the activity and proliferation of CAR-T cells and promoting their apoptosis.

Silymarin targets the FXR protein through microbial metabolite 7-keto-deoxycholic acid to treat MASLD in obese mice.

BACKGROUND: Silymarin is recognized for its excellent hepato-protective properties. Recent clinical studies have examined the effects of silymarin on metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting the necessity of further exploration into optimal dosages, active components, and mechanisms of action. METHODS AND RESULTS: This study assessed the anti-inflammatory activity of the principal constituents of silymarin at the cellular level. The therapeutic effects of varying silymarin doses and components on MASLD in mouse models induced by a high-fat diet (HFD) were also examined. These findings indicate the superior efficacy of 80 mg kg-1 silymarin in mitigating liver steatosis and reducing lipid accumulation compared to 30 mg kg-1 silymarin or a combination of silybin and isosilybin A. The mechanism of silymarin involves regulating gut microbiota homeostasis and influencing the TLR4/NF-κB signalling pathway through LPS. Bile acid-targeted metabolomics analysis revealed that silymarin significantly decreases the HFD-induced increase in 7-keto-deoxycholic acid (7-KDCA). Further investigations suggested that 7-KDCA as an antagonist targeted farnesoid X receptor (FXR) and that both silybin and isosilybin A could directly interact with FXR. CONCLUSION: These findings elucidate that 80 mg kg-1 of silymarin can exert therapeutic effects on MASLD mice and offer novel insights into the mechanism of silymarin in treating MASLD. Especially, it was found that silymarin could regulate bile acid metabolism, reduce the concentration of 7-KDCA, and thus perform negative feedback regulation on FXR.

Deep learning model for predicting the survival of patients with primary gastrointestinal lymphoma based on the SEER database and a multicentre external validation cohort.

PURPOSE: Due to the rarity of primary gastrointestinal lymphoma (PGIL), the prognostic factors and optimal management of PGIL have not been clearly defined. We aimed to establish prognostic models using a deep learning algorithm for survival prediction. METHODS: We collected 11,168 PGIL patients from the Surveillance, Epidemiology, and End Results (SEER) database to form the training and test cohorts. At the same time, we collected 82 PGIL patients from three medical centres to form the external validation cohort. We constructed a Cox proportional hazards (CoxPH) model, random survival forest (RSF) model, and neural multitask logistic regression (DeepSurv) model to predict PGIL patients' overall survival (OS). RESULTS: The 1-, 3-, 5-, and 10-year OS rates of PGIL patients in the SEER database were 77.1%, 69.4%, 63.7%, and 50.3%, respectively. The RSF model based on all variables showed that the top three most important variables for predicting OS were age, histological type, and chemotherapy. The independent risk factors for PGIL patient prognosis included sex, age, race, primary site, Ann Arbor stage, histological type, symptom, radiotherapy, and chemotherapy, according to the Lasso regression analysis. Using these factors, we built the CoxPH and DeepSurv models. The DeepSurv model's C-index values were 0.760 in the training cohort, 0.742 in the test cohort, and 0.707 in the external validation cohort, which demonstrated that the DeepSurv model performed better compared to the RSF model (0.728) and the CoxPH model (0.724). The DeepSurv model accurately predicted 1-, 3-, 5- and 10-year OS. Both calibration curves and decision curve analysis curves demonstrated the superior performance of the DeepSurv model. We developed the DeepSurv model as an online web calculator for survival prediction, which can be accessed at http://124.222.228.112:8501/ . CONCLUSIONS: This DeepSurv model with external validation is superior to previous studies in predicting short-term and long-term survival and can help us make better-individualized decisions for PGIL patients.

The Treatment of Diffuse Large B-Cell Lymphoma (Triple Expression) Involving the Breast, Spleen, and Bone in a Male Patient with Viral Hepatitis B: A Rare Case Report.

Background: Diffuse large B-cell lymphoma (DLBCL) involving the breast, spleen, and bone in a male patient with hepatitis B virus (HBV) infection is extremely rare in clinical practice. Case Presentation: We report a case of DLBCL involving the breast, spleen, and bone (triple expression of Bcl-2+, Bcl-6+, and 70% positive C-mcy) in a male patient with HBV admitted to our hospital. The patient was treated with EPOCH×4, lenalidomide+EPOCH×2 chemotherapy, intermittent methotrexate intrathecal injections to prevent central invasion, and autologous stem cell transplantation (ASCT). The patient is currently in complete remission, and the follow-up time was 43 months. Conclusion: A patient with DLBCL involving the breast, spleen, and bone can be treated with a combination of multiple regimens. If the patient's economic conditions permit it, ASCT can be considered.

Association Between Polymorphism in Diabetes Susceptibility Gene Insulin-Like Growth Factor 2mRNA-Binding Protein 2 and Risk of Diffuse Large B-Cell Lymphoma.

Background: Numerous studies have shown that polymorphisms in the diabetes susceptibility gene, insulin-like growth factor 2mRNA-binding protein 2 (IGF2BP2), are associated with the occurrence and development of various malignant tumors; however, their correlation with the onset of diffuse large B-cell lymphoma (DLBCL) is still unknown. Therefore, this study aimed to explore whether IGF2BP2 polymorphisms increase the risk of developing DLBCL. Methods: This study included 295 DLBCL patients and 331 healthy individuals. Peripheral blood was collected, and polymerase chain reaction-ligase detection reaction (PCR-LDR) was used to detect IGF2BP2 gene polymorphisms. Logistic regression was used to assess the association between IGF2BP2 polymorphism and the risk of DLBCL, adjusted for age, sex, and body mass index (BMI). P < .05 indicated statistical significance. Results: The rs4402960 polymorphism in the IGF2BP2 gene was associated with the occurrence and development of DLBCL. After adjusting for age, sex, and BMI, GT (odd ratio [OR] = 1.54; 95% confidence interval [CI] = 1.08-2.19; P = .016), TT (OR = 2.00; 95% CI = 1.09-3.68; P = .026), and T genotype carrying (GT + TT) (OR = 1.62; 95% CI = 1.17-2.25; P = .004) significantly increased the risk of DLBCL. This study also found that the polymorphism rs1470579 was related to the development of DLBCL. After adjusting for age, sex, and BMI, AC (OR = 1.55; 95% CI = 1.11-2.17; P = .010), CC (OR = 2.18; 95% CI = 1.17-4.06; P = .014), and C genotype carrying (AC + CC) (OR = 1.64; 95% CI = 1.19-2.26; P = .002) significantly increased the risk of DLBCL. Conclusions: Our study found that polymorphism in the IGF2BP2 gene was associated with an increased risk of developing DLBCL.

[HPLC fingerprint of citri grandis exocarpium from different cultivars].

OBJECTIVE: To study the quality difference among Citrus grandis 'Tomentosas' of different cultivars, in order to provide scientific basis for seeking for fine breeds. METHOD: The HPLC fingerprints were established for C. grandis 'Tomentosa' of different cultivars in the GAP base of Huazhou Green Life Co., Ltd. The software of similarity evaluation system of traditional Chinese medicine HPLC fingerprints 2004A edition of Chinese Pharmacopoeia Commission was adopted for the similarity analysis and judgment of cultivars. RESULT: The fingerprints showed similar general characteristics of samples of different cultivars. Specifically, the similarity of areas of the 18 common peaks ranged between 0.938-0.998. The success rate of judging cultivars using similarity software stood at 92%. CONCLUSION: This method can be applied to better identify quality and source of cultivars of C. grandis 'Tomentosa', and provide technical measures and scientific basis for seeking for fine breeds of Citri Grandis Exocarpium.

Case report: CD19-directed CAR-T cell therapy combined with BTK inhibitor and PD-1 antibody against secondary central nervous system lymphoma.

Current therapeutic strategies for central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) are extremely limited. Secondary central nervous system lymphoma (SCNSL) also shows a grave prognosis and high mortality. This report describes a young female patient with DLBCL and CNS relapse who received low-dose CD19-directed chimeric antigen receptor T (CAR-T) cell therapy followed with Bruton's tyrosine kinase inhibitor and programmed cell death protein 1 antibody after several lines of chemotherapy. However, limited reports on CAR-T cell therapy are applied for SCNSL, particularly those in combination with targeted agents. The current treatment combination for this case provides a new regimen for CNS relapse from DLBCL. Clinical Trial Registration: ClinicalTrials.gov number, NCT04666168.

Genomic Mutation Landscape of Primary Breast Lymphoma: Next-Generation Sequencing Analysis.

Primary breast lymphoma (PBL) is a rare subtype of non-Hodgkin's lymphoma (NHL) with rapid progression and high risk of central nervous system metastasis. We have investigated 40 PBL patients retrospectively, and 16 of them were sequenced by a target panel of 112 genes related with lymphoma. Next-generation sequencing (NGS) identified 203 mutations spanning 35 genes and revealed seven potential protein-changing genes (PIM1, MYD88, DTX1, CD79B, KMT2D, TNFAIP3, and ITPKB) with high frequency, referring crucial roles in lymphomagenesis. Our result suggested that PIM1 mutation is correlated with the age and pathological type of PBL patients. Gene TNFAIP3 and KMT2D mutation is only related to the pathological type and primary site, respectively. These high-mutant genes detected in PBL indicated a tendency to shorten overall survival (OS) and progression-free survival (PFS), which may lead to poor prognosis. Furthermore, the nuclear factor kappa-B (NF-κB) pathway and related regulatory factors are essential for the development of targeted therapy as well.

Simultaneous occurrence of Hodgkin's lymphoma and multiple myeloma: A case report and review of the literature.

Hodgkin's lymphoma (HL) is a type of hematological neoplasm that generally appears alone, with a low incidence. The majority of cases histopathologically present as B-cell lymphoma. Multiple myeloma (MM) is defined as the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin (Ig). The coexistence of HL and MM is rare, however, the present study reports such a case. On May 31, 2012, a 45-year-old man was diagnosed with HL, stage III, 31 months ago. At the same time, computed tomography and magnetic resonance imaging showed osteolytic lesions, a significant increase in IgA λ chains, and multiple myeloma cells on bone marrow aspiration. Following 8 cycles of chemotherapy, the patient received maintenance treatment with thalidomide and dexamethasone. During 2 years of follow-up, the patient has maintained a complete response for HL and a stable disease state for MM. The coexistence of HL and MM is rare. Further study of such cases may explain the associations between these two tumors and aid the production of effective treatment options.

Multiple differential expression networks identify key genes in rectal cancer.

BACKGROUND: Rectal cancer is an important contributor to cancer mortality. OBJECTIVE: The objective of this paper is to identify key genes across three phenotypes (fungating, polypoid and polypoid & small-ulcer) of rectal cancer based on multiple differential expression networks (DENs). METHODS: Differential interactions and non-differential interactions were evaluated according to Spearman correlation coefficient (SCC) algorithm, and were selected to construct DENs. Topological analysis was performed for exploring hub genes in largest components of DENs. Key genes were denoted as intersections between nodes of DENs and rectal cancer associated genes from Genecards. Finally, we utilized hub genes to classify phenotypes of rectal cancer on the basis of support vector machines (SVM) methodology. RESULTS: We obtained 19 hub genes and total 12 common key genes of three largest components of DENs, and EGFR was the common element. The SVM results revealed that hub genes could classify phenotypes, and validated feasibility of DEN methods. CONCLUSIONS: We have successfully identified significant genes (such as EGFR and UBC) across fungating, polypoid and polypoid & small-ulcer phenotype of rectal cancer. They might be potential biomarkers for classification, detection and therapy of this cancer.

PAQR3 gene expression and its methylation level in colorectal cancer tissues.

The aim of the present study was to investigate the PAQR3 gene expression and its methylation level in colorectal cancer tissues, as well as the association with colorectal cancer clinical data. In total, 54 cases of colorectal cancer tissue samples and normal adjacent tissue samples were collected between June, 2013 and July, 2014. RT-PCR and western blot analysis were used to detect the mRNA and protein levels of PAQR3 in colorectal samples, respectively. MSP was used to detect the methylation level of PAQR3 gene in colorectal samples, which was compared with colorectal data. The results showed that a decreased expression level of PAQR3 mRNA in colorectal cancer tissues and the expression reduction rate was 57.4% (31/54). Similarly, the expression level of PAQR3 protein was reduced in cancer tissues, and the reduction rate was 46.3% (25/54), while the protein expression reduction rate in cancer adjacent tissue was 5.6% (3/54), and the difference was statistically significant (P<0.05). Furthermore, the methylation rates of PAQR3 in cancer tissues and cancer adjacent tissues were 33.3% (18/54) and 5.6% (3/54), respectively. In addition, PAQR3 mRNA and protein levels in colorectal cancer tissues were associated with the differentiation degree, lymphatic metastasis and tumor infiltration depth. The methylation level of PAQR3 was associated with age, differentiated degree, lymphatic metastasis and tumor infiltration depth. In conclusion, the expression of PAQR3 mRNA and protein in colorectal cancer was reduced and methylation of PAQR3 occurred. Although the PAQR3 mRNA and protein levels were not associated with gender, age or the location of tumor, there was an association with differentiation degree, lymphatic metastasis and tumor infiltration depth. In addition, the methylation level of PAQR3 was not correlated with gender or tumor location, but was correlated with age, differentiation degree, lymphatic metastasis and tumor infiltration depth.

[Research on the application of grey system theory in the pattern recognition for chromatographic fingerprints of traditional Chinese medicine].

A model based on grey system theory was proposed for pattern recognition in chromatographic fingerprints (CF) of traditional Chinese medicine (TCM). The grey relational grade among the data series of each testing CF and the ideal CF was obtained by entropy and norm respectively, then the principle of "maximal matching degree" was introduced to make judgments, so as to achieve the purpose of variety identification and quality evaluation. A satisfactory result in the high performance liquid chromatographic (HPLC) analysis of 56 batches of different varieties of Exocarpium Citrus Grandis was achieved with this model. The errors in the chromatographic fingerprint analysis caused by traditional similarity method or grey correlation method were overcome, as the samples of Citrus grandis 'Tomentosa' and Citrus grandis (L.) Osbeck were correctly distinguished in the experiment. Furthermore in the study on the variety identification of Citrus grandis 'Tomentosa', the recognition rates were up to 92.85%, although the types and the contents of the chemical compositions of the samples were very close. At the same time, the model had the merits of low computation complexity and easy operation by computer programming. The research indicated that the grey system theory has good applicability to pattern recognition in the chromatographic fingerprints of TCM.