Long-Term Outcomes of Nasopharyngeal Carcinoma by Epstein-Barr Virus Status in the Chinese Population: A Multicenter Investigation.

Background: Because the vast majority of nasopharyngeal carcinoma (NPC) in Chinese patients is a direct result of Epstein-Barr virus (EBV) infection, there is a dearth of data for EBV-negative patients in this population. This multicenter study sought to examine the clinical characteristics of EBV-negative patients and compare long-term outcomes with a propensity-matched (1:1.5) EBV-positive cohort. Methods: NPC patients with known EBV status from four hospitals were collated (2013-2021). A logistic regression model was conducted to evaluate the relationship between patient characteristics and EBV status. The Kaplan-Meier method and Cox regression analysis were used to analyze survival data. Results: This study analyzed 48 (40%) EBV-negative and 72 (60%) EBV-positive patients. The median follow-up time was 63.5 months. Most EBV-negative NPC patients (77.1%) were diagnosed in advanced stages with a higher rate (87.5%) of positive lymph node disease, and no significant prognostic factors were discerned in this subpopulation. The EBV-negative disease was more associated with the keratinizing subtype (18.8% vs. 1.4%, p < 0.05). Compared to EBV-negative NPC patients, EBV-positive NPC patients were more likely to develop a local recurrence (9.7% vs. 0%, p = 0.026). There was no statistical difference in mortality (EBV-negative vs. EBV- positive, 8.3% vs. 4.2%, p = 0.34) during the follow-up period. Although the median PFS and median OS were not reached, the 3-year PFS rate was 68.8% vs. 70.8% (EBV-negative vs. EBV-positive, p = 0.06), the 3-year OS rate was 70.8% vs. 76.4% (EBV-negative vs. EBV-positive, p = 0.464), the 5-year PFS rate was 56.3% vs. 50% (EBV-negative vs. EBV-positive, p = 0.451), and the 5-year OS rate was 56.3% vs. 58.3% (EBV-negative vs. EBV-positive, p = 0.051), respectively. These data show that EBV-positive NPC patients seem to have a tendency to gain better survival compared with EBV-negative NPC patients. Conclusions: Most of the EBV-negative patients were in the middle and late stages at the time of diagnosis and were more associated with the keratinizing subtype. EBV status may be associated with prognosis in NPC. EBV positivity seems to be associated with better survival in NPC patients. Still, due to the small cohort of patients and the short observation period for a number of patients, further work is required to corroborate these conclusions.

A novel function for cyclin D1 as a transcriptional role in oncogenesis and tumor development by ChIP-Seq and RNA-Seq.

Introduction: Aberrations in cell cycle control is defined as one of the hallmarks of cancer, while cyclin D1 is an essential protein to cell cycle which promote G1 phase into S phase, and frequently overexpressed in many human cancers. However, new functions have been identified in transgenic mice models, including the transcription of genome, the development of chromosome instability and DNA repair. In this research, our aim is to find the function of cyclin D1 in transcription in human cancers. Methods: The correlation of the cyclin D1 expression levels and prognosis of cervical cancer patients were analyzed in tissue microarray (TMA) cohort. We chose C33A as our main research object. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq), to find out the genes differentially expressed in C33A, cyclin D1 knock-in C33A and cyclin D1 knock-down C33A. Results: We found that upregulation of cyclin D1 was associated with shorter overall survival (OS) and disease-free survival (DFS). Functionally, we identified 422 genes differentially expressed through analysis of the results of ChIP-seq and RNA-seq. These genes are highly enriched in Gene Ontology categories and involve in diverse cellular functions via KEGG classification, including replication and repair, signal transduction, cell growth and death. Conclusion: These findings suggested that the expression of cyclin D1 was associated with the prognosis of patients with cervical cancer. Cyclin D1 can serve both to activate and downregulate gene expression as a transcriptional role directly binding with genome DNA, which means that cyclin D1 may be a key protein during oncogenesis and tumor development.

Chemotherapy combined with radiotherapy for successful treatment of angioimmunoblastic T-cell lymphoma: a case report.

BACKGROUND: The incidence of angioimmunoblastic T-cell lymphoma is rare worldwide, and it has a poor prognosis. There is no proven or standard first-line therapy that works for the majority of patients with angioimmunoblastic T-cell lymphoma because of the rarity of this disease. The treatment and management are challenging for clinicians. CASE PRESENTATION: This report presents the diagnosis and treatment of a 65-year-old Chinese man who presented with cough and lymph node swellings in the left axillary region. The patient was diagnosed with angioimmunoblastic T-cell lymphoma. He underwent eight cycles of chemotherapy with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) followed by TOMO radiotherapy (helical tomotherapy, a kind of radiotherapy for cancer treatment using spiral computed tomographic scanning). After treatment, the therapeutic effects were evaluated by magnetic resonance imaging and computed tomography about every 3 months. The patient recovered well with no sign of tumor recurrence and no obvious severe treatment-related adverse effects. CONCLUSION: This treatment experience indicates an essential role for the combination of radiation therapy with CHOP, which may have a better prognosis than treatments without radiation therapy. But challenges warrant further validation in prospective studies.

Anti-tumour activity of zinc ionophore pyrithione in human ovarian cancer cells through inhibition of proliferation and migration and promotion of lysosome-mitochondrial apoptosis.

Zinc pyrithione (ZPT) is widely used as an antimicrobial. Zinc is a necessary trace element of the human whose homeostasis associated with several cancers. However, the anticancer effect of increased Zinc in ovarian cancer is still unclear. This study focussed on the anti-tumour effects of ZPT combined with Zinc in SKOV3 and SKOV3/DDP cells. The cell viability, apoptosis, migration, and invasion assays were detected by CCK-8, flow cytometry, wound healing and transwell assay, respectively. The distribution of Zinc in cells was monitored by staining of Zinc fluorescent dye and lysosome tracker. The changes in lysosomal membrane stability were reflected by acridine orange fluorescence and cathepsin D reposition. Expression of the proteins about invasion and apoptosis was evaluated by western blot. The results indicated that ZPT combined with Zinc could notably reduce cell viability, inhibit migration and invasion in SKOV3 and SKOV3/DDP cells. Besides, ZPT performed as a Zinc carrier targeted lysosomes, caused the increase of its membrane permeability and the release of cathepsin D accompanied by mitochondrial apoptosis in SKOV3/DDP cells. In conclusion, our work suggests that ZPT combined with Zinc could inhibit proliferation, migration, invasion, and promote apoptosis by trigger the lysosome-mitochondrial apoptosis pathway in ovarian carcinoma.

Downregulation of TMPRSS4 Enhances Triple-Negative Breast Cancer Cell Radiosensitivity Through Cell Cycle and Cell Apoptosis Process Impairment.

BACKGROUND: Radioresistance remains a challenge for cancer radiotherapy. The present study aims to investigate the role of TMPRSS4 in triple negative breast cancer (TNBC) cell radiosensitivity. MATERIALS AND METHODS: After transfection of MDA-MD-468 triple negative breast cancer cells line by using the lentivirus vector, the effect of TMPRSS4 down-regulation on TNBC radiosensitivity was evaluated by using cloning assay and CCK-8 assay. The CCK-8 assay was also used for performing cell proliferation analysis. Western blot was carried out to detect the expression of certain proteins related to cell cycle pathways (cyclin D1), cell apoptosis pathways (Bax, Bcl2, and Caspase3), DNA damage and DNA damage repair (TRF2, Ku80 , Ë H2AX) . The cell cycle and cell apoptosis were also investigated using flow cytometer analysis. RESULTS: TMPRSS4 expression was down-regulated in MDA-MB-468 cells which enhanced MDA-MB-468 cells radiosensitivity. TMPRSS4 silencing also improved IR induced cell proliferation ability reduction and promoted cell arrested at G2/M phase mediated by 6 Gy IR associated with cyclin D1 expression inhibition. Moreover, TMPRSS4 inhibition enhanced TNBC apoptosis induced by 6 Gy IR following by over-expression of (Bax, Caspase3) and down-regulation of Bcl2 as the pro-apoptotic and anti-apoptotic proteins, respectively. Otherwise, TMPRSS4 down-regulation increases  DNA damage induced by 6 Gy IR and delays DNA damage repair respectively illustrated by downregulation of TRF2 and permanent increase of Ku80 and Ë H2AX expression at 1 h and 10 h post-IR. CONCLUSION: Down-regulation of TMPRSS4 increases triple negative breast cancer cell radiosensitivity and the use of TMPRSS4 inhibitor can be encouraged for improving radiotherapy effectiveness in TNBC radioresistant patients.

Ribociclib (LEE011) suppresses cell proliferation and induces apoptosis of MDA-MB-231 by inhibiting CDK4/6-cyclin D-Rb-E2F pathway.

Triple-negative breast cancer (TNBC) stands for a refractory subtype, which predicts poor prognosis and has no effective therapies yet for improving it. Given the restrictions of traditional treatments, novel therapeutic strategies need excavating to alleviate the intrinsic or acquired resistance. Ribociclib, a selective CDK4/6 inhibitor, has successfully prevented cancers from deteriorating by intervening the CDK4/6-cyclin D-Rb-E2F pathway, especially for estrogen receptor-positive (ER +) breast cancer. However, there still remains limited accessibility referring to TNBC. Performing experiments on MDA-MB-231 cells, we found that LEE011 could suppress cell proliferation, and this suppression tended to be dose-dependently. Western blotting analysis presented significant decrease with the expression of CDK4/6 after LEE011 treated, and other proteins associated with this axis such as cyclin D1, p-Rb, Rb, E2F1 showed aberrant changes. Moreover, LEE011 induced G0-G1 phase cell cycle arrest, promoted cell apoptosis, and reduced cell migration in vitro. In addition, tumor growth was remarkably impeded without obvious side-effects in MDA-MB-231 xenograft models. Our research has identified that LEE011 was not completely invalid for MDA-MB-231. Considering its pivotal status in TNBC, the CDK4/6-cyclin D-Rb-E2F pathway informed us the possibility and practicality of Ribociclib (LEE011) as pharmacological intervention, but challenges warrant further validation in prospective studies.

Role of TMPRSS4 Modulation in Breast Cancer Cell Proliferation.

Background: TMPRSS4 is a novel Type II transmembrane serine protease found at the surface of the cells and is involved in the development and cancer progression. However, TMPRSS4 functions in breast cancer remain poor understand. The present study investigated the function of TMPRSS4 in the breast cancer cells and the potential mechanistic action underling. Materials and Methods: The lentiviral vectors causing TMPRSS4 down-regulation and over-expression were established and transfected in MDA-MB-468 and MCF-7 cells, respectively. By using the CCK- 8 assay, cell proliferation was analyzed. Moreover, western blot was used to detect the expression of certain proteins related to cell apoptosis (Bax and Bcl2) signaling pathway and telomere maintenance (POT1, TPP1, and UBE2D3). Cell cycle and cell apoptosis were also analyzed by using the Flow cytometry analysis. TMPRSS4 expression was detected at the mRNA level and protein level by performing qPCR and western blot technique, respectively. Results: TMPRSS4 expression is inhibited in stable transfected MDA-MB-468-shTMPRSS4 cells compared to the control MDA-MB-468-NC and its expression is up-regulated in stable transfected MCF-7-TMPTSS4 compared to its control MCF-7-NC. Moreover, TMPRSS4 silencing in breast cancer reduces cells proliferation by promoting cell cycle arrest in G2/M phase, cell apoptosis, and telomere maintenance impairment while the TMPRSS4 overexpression increases cells proliferation through cell apoptosis reduction and telomere maintenance reinforcement associated with insignificant change in cell cycle progression. Conclusion: TMPRSS4 plays important roles in cancer progression and may be considered as a good therapeutic target for cancer gene therapy especially breast cancer.

Ribociclib, a selective cyclin D kinase 4/6 inhibitor, inhibits proliferation and induces apoptosis of human cervical cancer in vitro and in vivo.

Cervical cancer remains one of the main factors leading to tumor-related death worldwide. Many strategies of cancer treatment such as chemotherapy are developed and used nowadays. However, for the cancer chemotherapy resistance, reduction of the limitation of cancer chemotherapy efficacy is one of the aims of several oncology teams. Moreover, the cyclin-dependent kinase 4/6-cyclin D-retinoblastoma protein-E2F pathway is an important mechanism for cell cycle control and its dysregulation is one of the key factors for cancers development including cervical cancer. Ribociclib is one of the selective CDK4/6 inhibitors and is a new therapeutic approach showing promise as a good strategy of therapy in many human cancers. However, there are not the studies regarding the investigation of effects of Ribociclib in cervical cancer yet. In the present study, by western blotting and immunofluorescence assay, we found respectively that CDK4, CDK6 and cyclin D1 are highly expressed and are mostly localized in the nucleus with some localized in the cytoplasm of cervical cancer cell lines. Moreover, Ribociclib induced cell cycle arrest in G0-G1 phase and cell apoptosis, and inhibited C33A cell proliferation in dose - dependent manner following by decreased expression of certain related genes such as CDK4, CDK6, E2F1, P-Rb, and increased Bax expression. In C33A xenografts, Ribociclib inhibited tumor growth associated with decreased expressions of CDK4, CDK6, cyclin D1, Rb and Ki-67, and also significantly increased tumor cell apoptosis. However, we didn't find side effect of Ribociclib concerning heart, liver and kidney perturbation and any Ribociclib anti-tumor effects on HeLa in vitro and in vivo which may be due to Hela cell infection by HPV. Based on our findings, the Rb-E2F pathway can be considered as an important factor in human cervical cancer pathogenesis and as a mechanism of Ribociclib, a potential strategy of treatment for the improvement of new therapeutic measures for the treatment of HPV-negative cervical cancer which application for HPV-positive cervical cancer is desired in further study.

Effect of therapies-mediated modulation of telomere and/or telomerase on cancer cells radiosensitivity.

Cancer is one of the leading causes of death in the world. Many strategies of cancer treatment such as radiotherapy which plays a key role in cancer treatment are developed and used nowadays. However, the side effects post-cancer radiotherapy and cancer radioresistance are two major causes of the limitation of cancer radiotherapy effectiveness in the cancer patients. Moreover, reduction of the limitation of cancer radiotherapy effectiveness by reducing the side effects post-cancer radiotherapy and cancer radioresistance is the aim of several radiotherapy-oncologic teams. Otherwise, Telomere and telomerase are two cells components which play an important role in cancer initiation, cancer progression and cancer therapy resistance such as radiotherapy resistance. For resolving the problems of the limitation of cancer radiotherapy effectiveness especially the cancer radio-resistance problems, the radio-gene-therapy strategy which is the use of gene-therapy via modulation of gene expression combined with radiotherapy was developed and used as a new strategy to treat the patients with cancer. In this review, we summarized the information concerning the implication of telomere and telomerase modulation in cancer radiosensitivity.

Integrated analysis of long noncoding RNA associated-competing endogenous RNA as prognostic biomarkers in clear cell renal carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant carcinomas and its molecular mechanisms remain unclear. Long noncoding RNA (lncRNA) could bind sites of miRNA which affect the expression of mRNA according to the competing endogenous (ceRNA) theory. The aim of the present study was to construct a ceRNA network and to identify key lncRNA to predict survival prognosis. We identified differentially expressed mRNA, lncRNA and miRNA between tumor tissues and normal tissues from The Cancer Genome Atlas database. Then, using bioinformatics tools, we explored the connection of 89 lncRNA, 10 miRNA and 22 mRNA, and we constructed the ceRNA network. Furthermore, we analyzed the functions and pathways of 22 differentially expressed mRNA. Then, univariate and multivariate Cox regression analyses of these 89 lncRNA and overall survival were explored. Nine lncRNA were finally screened out in the training group. The patients were divided into high-risk and low-risk groups according to the 9 lncRNA and low-risk scores having better clinical overall survival (P < .01). Furthermore, the receiver operating characteristic curve demonstrates the predicted role of the 9 lncRNA. The 9-lncRNA signature was successfully proved in the testing group and the entire group. Finally, multivariate Cox regression analysis and stratification analysis further proved that the 9-lncRNA signature was an independent factor to predict survival. In summary, the present study provides a deeper understanding of the lncRNA-related ceRNA network in ccRCC and suggests that the 9-lncRNA signature could serve as an independent biomarker to predict survival in ccRCC patients.