TBC1D10B promotes tumor progression in colon cancer via PAK4­mediated promotion of the PI3K/AKT/mTOR pathway.

This study aimed to explore the expression, function, and mechanisms of TBC1D10B in colon cancer, as well as its potential applications in the diagnosis and treatment of the disease.The expression levels of TBC1D10B in colon cancer were assessed by analyzing the TCGA and CCLE databases. Immunohistochemistry analysis was conducted using tumor and adjacent non-tumor tissues from 68 colon cancer patients. Lentiviral infection techniques were employed to silence and overexpress TBC1D10B in colon cancer cells. The effects on cell proliferation, migration, and invasion were evaluated using CCK-8, EDU, wound healing, and Transwell invasion assays. Additionally, GSEA enrichment analysis was used to explore the association of TBC1D10B with biological pathways related to colon cancer. TBC1D10B was significantly upregulated in colon cancer and closely associated with patient prognosis. Silencing of TBC1D10B notably inhibited proliferation, migration, and invasion of colon cancer cells and promoted apoptosis. Conversely, overexpression of TBC1D10B enhanced these cellular functions. GSEA analysis revealed that TBC1D10B is enriched in the AKT/PI3K/mTOR signaling pathway and highly correlated with PAK4. The high expression of TBC1D10B in colon cancer is associated with poor prognosis. It influences cancer progression by regulating the proliferation, migration, and invasion capabilities of colon cancer cells, potentially acting through the AKT/PI3K/mTOR signaling pathway. These findings provide new targets and therapeutic strategies for the treatment of colon cancer.

First-line sintilimab with pegaspargase, gemcitabine, and oxaliplatin in advanced extranodal natural killer/T cell lymphoma (SPIRIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We aimed to assess the safety and activity of sintilimab plus P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) in the first-line setting for advanced ENKTL. METHODS: The multicentre, single-arm, phase 2 trial was done at three medical centres in China. Patients aged 18-75 years with treatment-naive pathologically confirmed advanced ENKTL and an with Eastern Cooperative Oncology Group performance status score of 0-2 were eligible. Patients received intravenous sintilimab (200 mg on day 1), intramuscular pegaspargase (2000 U/m2 on day 1), intravenous gemcitabine (1 g/m2 on days 1 and 8), and intravenous oxaliplatin (130 mg/m2 on day 1) every 3 weeks for six cycles, followed by intravenous sintilimab (200 mg) every 3 weeks for up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint was the complete response rate in the intention-to-treat population. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), and overall survival. This trial is registered with ClinicalTrials.gov, NCT04127227. Enrolment has been completed, and follow-up is ongoing. FINDINGS: Between Nov 29, 2019, and Sept 7, 2022, 34 eligible patients were enrolled (median age 39 years [IQR 32-55]; 25 [74%] of 34 patients were male; nine [26%] were female; and all were of Asian ethnicity). At the data cutoff (July 20, 2023), the median follow-up was 21 months (IQR 13-32). The complete response rate was 85% (29 of 34 patients, 95% CI 70-94). Five patients (15%; 95% CI 7-30) attained partial response and the ORR was 100% (34 of 34 patients). 24-month PFS was 64% (95% CI 48-86), 24-month DFS was 72% (54-95), and 36-month overall survival was 76% (52-100). The most common grade 3 or 4 treatment-related adverse events were neutropenia (17 [50%] of 34 patients), anaemia (10 [29%] patients), and hypertriglyceridemia (10 [29%] patients). Hypothyroidism was the most frequent immune-related adverse event (18 [53%]), including grade 3 hypothyroidism in one (3%) patient that caused treatment termination. No severe adverse events occurred. There were three deaths: one due to haemophagocytic syndrome, one due to disease progression, and one due to unknown cause, which were not considered to be treatment related. INTERPRETATION: Combination of sintilimab with P-GEMOX seems to be an active and safe first-line regimen for patients with advanced ENKTL. FUNDING: National Key Research and Development Program and National Natural Science Foundation of China, Guangzhou Science and Technology Program and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology.

Pan-cancer analysis of the prognostic significance and oncogenic role of GXYLT2.

Growing evidence supports an oncogenic role for glucoside xylosyltransferase 2 (GXYLT2) in a number of malignancies. To evaluate the prognostic value and oncogenic function of GXYLT2 in diverse cancer types, we analyzed sequencing data from public databases on 33 tumor tissues and their corresponding normal tissues. We found that GXYLT2 was overexpressed in a number of tumors, and that its expression was positively correlated with disease progression and mortality in several major cancer types including stomach adenocarcinoma (STAD). GXYLT2 was also linked to tumor size, grade, and the immune and molecular subtypes of STAD. GO and KEGG pathway analyses of GXYLT2 co-expressed genes in STAD suggested that GXYLT2 possibly plays a role in epithelial-mesenchymal transition, extracellular matrix production and degradation, angiogenesis, apoptosis, as well as in tumor inflammation, such as cytokine production and T cell activation. Finally, prognostic nomograms were created and validated for predicting 1, 3, and 5-year survival of patients with STAD. Our findings indicate that GXYLT2 may play a role in tumorigenesis and tumor immunity, and it may serve as a prognostic marker and potential immunotherapeutic target for STAD and some other types of cancer.

Significance of platelet adhesion-related genes in colon cancer based on non-negative matrix factorization-based clustering algorithm.

Background: Although surgical methods are the most effective treatments for colon adenocarcinoma (COAD), the cure rates remain low, and recurrence rates remain high. Furthermore, platelet adhesion-related genes are gaining attention as potential regulators of tumorigenesis. Therefore, identifying the mechanisms responsible for the regulation of these genes in patients with COAD has become important. The present study aims to investigate the underlying mechanisms of platelet adhesion-related genes in COAD patients. Methods: The present study was an experimental study. Initially, the effects of platelet number and related genomic alteration on survival were explored using real-world data and the cBioPortal database, respectively. Then, the differentially expressed platelet adhesion-related genes of COAD were analyzed using the TCGA database, and patients were further classified by employing the non-negative matrix factorization (NMF) analysis method. Afterward, some of the clinical and expression characteristics were analyzed between clusters. Finally, least absolute shrinkage and selection operator regression analysis was used to establish the prognostic nomogram. All data analyses were performed using the R package. Results: High platelet counts are associated with worse survival in real-world patients, and alternations to platelet adhesion-related genes have resulted in poorer prognoses, based on online data. Based on platelet adhesion-related genes, patients with COAD were classified into two clusters by NMF-based clustering analysis. Cluster2 had a better overall survival, when compared to Cluster1. The gene copy number and enrichment analysis results revealed that two pathways were differentially enriched. In addition, the differentially expressed genes between these two clusters were enriched for POU6F1 in the transcription factor signaling pathway, and for MATN3 in the ceRNA network. Finally, a prognostic nomogram, which included the ALOX12 and ACTG1 genes, was established based on the platelet adhesion-related genes, with a concordance (C) index of 0.879 (0.848-0.910). Conclusion: The mRNA expression-based NMF was used to reveal the potential role of platelet adhesion-related genes in COAD. The series of experiments revealed the feasibility of targeting platelet adhesion-associated gene therapy.

TRIM69: a marker of metastasis and potential sensitizer to 5-Fluorouracil and PD-1 blockers in colon adenocarcinoma.

BACKGROUND: Several proteins in the tripartite-motif (TRIM) family are associated with the development of colorectal cancer (CRC), but research on the role of TRIM69 was lacking. The present study examined the correlation between TRIM69 expression and colon adenocarcinoma (COAD). METHODS: mRNA sequencing data for COAD patients was extracted from The Cancer Genome Atlas to analyze correlations between TRIM69 expression and patients' clinical features as well as survival. Potential associations with immune cells and chemosensitivity also were predicted using various algorithms in the TIMER, Limma, clusterProfiler, GeneMANIA, and Gene Set Cancer Analysis platforms. Subsequently, polymerase chain reaction analysis and immunohistochemical staining were used to detect TRIM69 expression in COAD tissue samples from real-world patients. RESULTS: TRIM69 expression was lower in COAD tissues than in normal tissues and correlated with the pathologic stage and metastasis (M category). Additionally, TRIM69 was found to be involved in several immune-related pathways, notably the NOD-like signaling pathway. These results suggest that high TRIM69 expression has the potential to enhance tumor sensitivity to 5-fluorouracil and programmed cell death protein 1 (PD-1) blockers. CONCLUSIONS: From our findings that TRIM69 expression was significantly reduced in COAD compared with non-cancer tissues and associated with pathologic stage and metastasis, we conclude that increasing TRIM69 expression and/or activity may help to improve therapeutic outcomes. Accordingly, TRIM69 represents a potentially valuable marker of metastasis and target for adjuvant therapy in COAD.

LncRNA BCYRN1-induced autophagy enhances asparaginase resistance in extranodal NK/T-cell lymphoma.

Background: Asparaginase (ASP) is the cornerstone drug in the treatment of extranodal NK/T-cell lymphoma (ENKTCL), and the mechanisms of resistance to ASP remain largely unknown. Long non-coding RNAs play important roles in chemotherapy resistance in various cancers. However, the expression of BCYRN1 and its role in ENKTCL still remain unidentified. Methods: Lentivirus-mediated BCYRN1 overexpression and knockdown were performed in SNK-6 cells. Cell autophagy was analyzed by adenovirus expressing GFP-LC3B fusion protein. RNA pull-down and RNA Binding Protein Immunoprecipitation Assay were performed to investigate the relationship between BCYRN1 and p53. Western blot analysis was performed to assess the effect of BCYRN1 on different autophagy pathways. Finally, in vivo xenograft tumor model was constructed to analyze the effect of BCYRN1 on tumor growth and ASP resistance. Results: BCYRN1 was overexpressed in ENKTCL than normal NK cells, and patients with higher expression had significantly inferior progression-free survival (PFS). The IC50 value of ASP was significantly increased in BCYRN1-overexpressed SNK-6 cells and BCYRN1 overexpression could resist the inhibitory effect of ASP on proliferation. ASP could induce concurrent apoptosis and autophagy in ENKTCL, and the latter process was enhanced by overexpression of BCYRN1, mainly through affecting both PI3K/AKT/mTOR and p53/mTOR pathways. BCYRN1 could induce the degradation of p53 via ubiquitination, thus resulting in enhancement of autophagy and ASP resistance, which could be reversed by drug-induced autophagy inhibition. The effect of BCYRN1 on tumor growth and autophagy were confirmed in vivo xenograft model. Conclusions: It was found that BCYRN1 was a valuable prognostic biomarker in ENKTCL. BCYRN1 could promote resistance to ASP by inducing autophagy, which could be reversed by inhibition of autophagy. Our findings highlight the feasibility of combining autophagy inhibition and ASP in the treatment of ENKTCL.

Development and Validation of a Serum Biomarker Panel for the Detection of Esophageal Squamous Cell Carcinoma through RNA Transcriptome Sequencing.

Serum tumor markers for the diagnosis of esophageal squamous cell carcinoma (ESCC) have low sensitivity. This study aims to identify new serum markers for ESCC diagnosis from RNA sequencing (RNA-seq) data. RNA-seq was performed using six pairs of ESCC and matched normal tissues. The candidates for ESCC were screened from the differentially expressed genes. The candidates were analyzed by ELISA from the serum of a test group and a validation group. Real-time PCR, Western blotting and immunohistochemistry were used to detect the expression of the candidates in tumor cell lines and tumor tissues. Ten genes were selected from the RNA-seq data. Serum levels of ADAM12, CHI3L1, MMP13 and SPP1 were significantly higher in the ESCC patients than in the healthy controls. A diagnostic model combining CHI3L1, MMP13, and SPP1 was established. The area under the curve (AUC) values for serum CHI3L1, MMP13, and SPP1 and the diagnostic model for discriminating ESCC patients from controls were 0.732, 0.881, 0.661 and 0.928, respectively. In the validation cohort, the AUC values were 0.753, 0.789, 0.696 and 0.843, respectively. Moreover, the AUC of the model for classifying patients with early ESCC was 0.918 in the test group and 0.857 in the validation group. Overexpression of CHI3L1, MMP13 and SPP1 was observed in the tumor cell lines and tissues. The diagnostic model composed of CHI3L1, MMP13 and SPP1 discriminates ESCC patients with high sensitivity. Our data highlight the potential of this diagnostic model for the noninvasive diagnosis of ESCC.

Efficacy and Safety of Belimumab Plus Standard Therapy in Patients With Systemic Lupus Erythematosus: A Meta-analysis.

PURPOSE: The treatment of belimumab plus standard therapy in patients with systemic lupus erythematosus (SLE) has been studied extensively in recent years. Our aim was to estimate the efficacy and safety of this therapy compared with placebo plus standard therapy in patients with SLE. METHODS: PubMed, Web of Science, Embase, Chinese Biomedical Literature Database (CBM, Chinese), and Wanfang Database (Chinese) were searched for all randomized clinical trials that mainly studied the efficacy and safety of belimumab plus standard therapy before June 2015. We extracted or calculated the rate of the SLE Response Index and adverse event rate at 52 weeks in all the included studies. The odds ratio (OR) with 95% CI between the 2 groups in this meta-analysis was conducted by using a random-effects model. Sensitivity and publication bias analyses were also performed. All statistical tests were performed by using Stata software version 12.0 (StataCorp., College Station, Texas). FINDINGS: In the overall samples (4 studies, N = 4692 ), a significantly higher SLE Response Index rate at 52 weeks was found in belimumab plus standard therapy group compared with the placebo plus standard therapy group in all studies (OR = 1.49; 95% CI, 1.26-1.77 ; P < 0.001 ). When assessed with the incidence of serious adverse events, the data revealed that there was no significant difference between the 2 groups, with pooled OR = 1.08; 95% CI, 0.83-1.39; P = 0.573; OR = 1.23; 95% CI, 1.02-1.48; P = 0.029; and OR = 1.07; 95% CI, 0.88-1.29; P = 0.506. IMPLICATIONS: The results suggest that treatment with belimumab plus standard therapy is more effective than placebo plus standard therapy in SLE patients, which represents major progress in the treatment of SLE. Regardless of the statistical analyses, further research is necessary to optimize treatment effects.

MiR-212 exerts suppressive effect on SKOV3 ovarian cancer cells through targeting HBEGF.

MicroRNAs (miRNAs) play critical roles in the development and progression of ovarian cancer. We found that miR-212 was significantly downregulated in serum and tissues from epithelial ovarian cancer (EOC) patients. Overexpression of miR-212 in ovarian cancer cells inhibited cell proliferation, migration, and invasion. Luciferase reporter assay confirmed HBEGF as a direct target of miR-212. Overexpression of miR-212 decreased HBEGF expression at both the protein and messenger RNA (mRNA) levels. Knockdown of HBEGF expression in SKOV3 cell line significantly inhibited cell growth, migration, and invasion. HBEGF mRNA level was upregulated in EOC tissues and inversely correlated with miR-212 expression in tissues. Upregulation of HBEGF could attenuate the effect induced by miR-212. These findings indicate that miR-212 displays a tumor-suppressive effect in human ovarian cancer. And miR-212 suppresses cell proliferation, migration, and invasion by targeting the HBEGF transcript, highlighting the therapeutic potential of miR-212 and HBEGF in epithelial ovarian cancer treatment.

[Efficacy of chemotherapy as a first-line treatment in patients with ocular adnexal MALT lymphoma].

The aim of this study was to analyze the efficacy of first-line chemotherapy in treating patients with ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). Eight consecutive newly diagnosed ocular adnexal MALT lymphoma patients were treated with chemotherapy, in which 3 patients in stage IE were treated with a combination of cyclophosphamide, vincristine and prednisolone (COP) or cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP), 5 patients in stage IV were treated with COP/CHOP in combination with rituximab. The results showed that chemotherapy resulted in an overall response rate of 100%, 3 patients in stage IE were in partial remission (PR), 5 patients in stage IV were in complete remission (CR). After a median follow-up of 21 months, 3 patients in stage IE were still in PR status, 5 patients in stage IV were still in CR status, and no relapses or disease progression were observed. It is concluded that the first-line chemotherapy has been confirmed to be effective and well tolerated in patients with localized ocular adnexal MALT lymphoma. Rituximab combined with chemotherapy can increase remission rate, it is feasible option as first-line treatment for ocular adnexal MALT lymphoma.

[The clinical features and outcomes in 21 patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma].

OBJECTIVE: To evaluate the clinical features, therapies and prognosis in patients with mucosa-associated lymphoid tissue (MALT) lymphoma in ocular adnexal marginal zone (OAML). METHODS: A retrospective analysis was made upon clinical data from 21 patients with OAML admitted into Beijing Tongren Hospital from June, 2008 to December, 2011. RESULTS: There were 12 (57.1%) men and 9 (42.9%) women, with a median age of 57 (23 - 79) years old. Majority of patients had localized pathological changes. Among them, 16 patients (76.2%) were in stage IE, and 5 (23.8%) in stage IVE. Surgical resection as the sole treatment was performed in 13 patients (61.9%), and positron emission tomography CT(PET-CT) imaging demonstrated normal fluorine 18-fluorodeoxyglucose (FDG) uptake after surgical resection, who were managed with no further therapy. All the 13 patients were followed up for median 14 (5 - 38) months, and all in complete remission. Combination chemotherapy was given to 8 (38.1%) patients. Three patients in stage IE treated with COP (cyclophosphamide, vincristine and prednisone) or CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) were all in partial remission. Five patients in stage IVE were treated with COP/CHOP in combination with rituximab, and all in complete remission. The 3-year overall survival rate and disease-free survival rate in the total patients were 100.0% and 74.9% respectively. CONCLUSIONS: The patients with OAML generally have localized disease, show indolent clinical course, and present low lymphoma-related mortality. Surgical resection is a very important treatment in the patients with local disease. Systemic chemotherapy should be considered in patients at advanced stages. Rituximab in combination with chemotherapy can improve the remission rate.

The importance of γ-Glutamyltransferase (GGT) activity: a potential marker of Left Ventricular (LV) diastolic function in diabetic patients with cardiovascular disease.

OBJECTIVES: To examine the relation between left ventricular (LV) diastolic function and γ-glutamyltransferase (GGT) in diabetic individuals with or without previously diagnosed cardiovascular disease. DESIGN: A cross-sectional population-based study. SETTING: A university hospital. SUBJECTS: A total of 205 diabetic patients were included in the study. Patients who had cardiovascular disease constituted the study group (CD group; n = 112) and patients who had no complications constituted the control group (ND group; n = 93). Left ventricular diastolic function was assessed by pulsed Doppler tissue imaging and was determined by ratio E wave/A wave. MAIN OUTCOME MEASURES: GGT levels were higher in CD Group than ND Group (25.9 ± 2.1 vs. 20.1 ± 1.5 units/L, p = 0.023). Significant difference between mean diastolic function parameters, such as E wave/A wave (0.86 ± 0.27 vs. 1.01 ± 0.36, p = 0.015), of the diabetic patients with and without cardiovascular disease was present. In this study, E wave/A wave correlated with age, waist-to-hip ratio (WHR), systolic blood pressure, and total cholesterol. Negative correlations were also found between LV diastolic function and GGT (ß = -0.009, p = 0.008). CONCLUSION: The data showed that in type 2 diabetic patients, with evident cardiac disease, metabolic parameters affect diastolic functions more than systolic functions. Besides known cardiovascular disease risk factors, GGT might be an additional marker of diastolic dysfunction in diabetes patients with cardiovascular disease.