Shorter duration of Blinatumomab administration to 14 days has same efficacy and safety profile in treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia: A retrospective single-center study.

INTRODUCTION: Treatment of patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL) remains a significant clinical challenge. Many new strategies are changing the treatment landscape of r/r BCP-ALL in recent years. Blinatumomab has improved outcomes in r/r BCP-ALL, though high treatment costs and extended hospital stays are significant concerns. We considered that shortening the duration of blinatumomab administration during induction therapy might solve these problems. METHODS: We retrospectively analyzed 19 patients with r/r BCP-ALL treated with different duration of blinatumomab, where 10 patients received blinatumomab for 14 days (Bli 14 D group) and 9 received it for a longer duration (LT group, 21-28 days). RESULTS: The overall response rate (ORR) was 63.2% (12/19) of patients in total, and the ORR rates in 14 D and LT groups were almost the same (60% and 66.6%, respectively). The median overall survival (OS) was not reached in either groups. The median event-free survival (EFS) time was 4.1 months in LT group and not reached in D14 group. The most common adverse events were consistent with previous reports, including cytokine release syndrome (CRS), neurologic toxicity, and hematological toxicity. CONCLUSION: A 14-day blinatumomab administration may be a promising and well-tolerated regimen in r/r BCP-ALL, offering the same ORR and survival rates.

Development of a scoring system for predicting primary resistance to venetoclax plus hypomethylating agents (HMAs) in acute myeloid leukemia patients.

In recent years, one of the most promising advances in the treatment of acute myeloid leukemia (AML) is the combination of a hypomethylating agent (HMA) with the BCL2 inhibitor venetoclax (VEN). To better understand the key factors associated with the response of VEN plus HMA, 212 consecutive AML patients were retrospectively recruited to establish and validate a scoring system for predicting the primary resistance to VEN-based induced therapy. All AML patients were divided randomly into a training set (n = 155) and a validation set (n = 57). Factors were selected using a multivariate logistic regression model, including FAB-M5, myelodysplastic syndrome-secondary acute myeloid leukemia (MDS-sAML), RUNX1-RUNX1T1 and FLT3-ITD mutation (FLT3-ITDm). A nomogram was then constructed including all these four predictors. The nomogram both presented a good performance of discrimination and calibration, with a C-index of 0.770 and 0.733 in the training and validation set. Decision curve analysis also indicated that the nomogram was feasible to make beneficial decisions. Eventually a total scoring system of 8 points was developed, which was divided into three risk groups: low-risk (score 0-2), medium-risk (score 3-4), and high-risk (score 5-8). There was a significant difference in the nonremission (NR) rate of these three risk groups (22.8% vs. 60.0% vs. 77.8%, p < 0.001). After adjustment of the other variables, patients in medium- or high-risk groups also presented a worse event-free survival (EFS) than that in the low-risk group (hazard ratio [HR] = 1.62, p = 0.03). In conclusion, we highlighted the response determinants of AML patients receiving a combination therapy of VEN plus HMAs. The scoring system can be used to predict the resistance of VEN, providing better guidance for clinical treatment.

Porphyromonas gingivalis promotes progression of esophageal squamous cell cancer via TGFß-dependent Smad/YAP/TAZ signaling.

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-ß (TGFß)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFß through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFß axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.

The relationship between Porphyromonas gingivalis and oesophageal squamous cell carcinoma: a literature review.

Oesophageal cancer is the most common gastrointestinal malignancy in China and one of the major causes of death due to cancer worldwide. The occurrence of oesophageal cancer is a multifactor, multistage, and multistep process influenced by heredity, the environment, and microorganisms. Specifically, bacterial infection may be involved in the process of tissue carcinogenesis by directly or indirectly influencing tumour occurrence and development. Porphyromonas gingivalis is an important pathogen causing periodontitis, and periodontitis can promote the occurrence of various tumours. An increasing number of studies to date have shown that P. gingivalis plays an important role in the occurrence and development of oesophageal cancer. Overall, exploring how P. gingivalis promotes oesophageal cancer occurrence and development and how it affects the prognosis of these patients is of great importance for the diagnosis, prevention, and treatment of this type of cancer. Herein, the latest progress is reviewed.

Circular RNA Hsa_circ_0066755 as an Oncogene via sponging miR-651 and as a Promising Diagnostic Biomarker for Nasopharyngeal Carcinoma.

Background: Circular RNAs (circRNAs) represent a class of broad and diversified endogenous RNAs that regulate gene expressions in eukaryotes. Hsa_circ_006675 has been proven as an important circRNA molecule in nasopharyngeal carcinoma (NPC), however, its function still remains elusive. This study aims to discuss the biofunctions of hsa_circ_0066755 in NPC. Methods: We detected the expression levels of hsa_circ_0066755 in NPC patients by quantitative real-time polymerase chain reaction (qRT-PCR), and the corresponding ROC curves were plotted. Functional experiments including CCK-8, colony formation, Transwell assay and Xenograft experiment were conducted. Bioinformatics analysis was performed to seek miRNAs which might have binding sites with hsa_circ_0066755. Luciferase reporter assays were finally carried out to verify the binding sites. Results: We found significant increases of hsa_circ_0066755 in the plasma and tissues of the patients. Moreover, its levels were positively correlated with clinical staging (P=0.019). The receiver operating characteristic (ROC) analysis showed that the area under the curves (AUCs) of tissue and plasma hsa_circ_0066755 for distinguishing NPC from non-cancerous controls were 0.8537 and 0.9044, respectively. Both tissue and plasma hsa_circ_0066755 testing presented a comparable diagnostic accuracy to the magnetic resonance imaging (MRI). Our in-vitro experiment showed that the overexpression of hsa_circ_0066755 facilitated the growth, proliferation, clone formation, invasion and migration of CNE-1 NPC cells, while its down-regulation showed completely opposite effects. The xenograft experiment showed that exogenous hsa_circ_0066755 could significantly enhance the in-vivo tumorigenic ability of CNE-1 cells. Rescue assay further confirmed hsa_circ_0066755 as a tumor facilitator by sponging miR-651. Conclusions: Collectively, this study reported for the first time that hsa_circ_0066755 played a role of oncogene in NPC and could be used as an effective diagnostic marker for NPC, and that hsa_circ_0066755 / miR-651 axis also involved in the progression of NPC.

DNA Repair Gene Polymorphisms in Relation to Non-Small Cell Lung Cancer Survival.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the DNA repair genes are suspected to be related to the survival of lung cancer patients due to their possible influence on DNA repair capacity (DRC). However, the study results are inconsistent. METHODS: A follow-up study of 610 non-small cell lung cancer (NSCLC) patients was conducted to investigate genetic polymorphisms associated with the DNA repair genes in relation to NSCLC survival; 6 SNPs were genotyped, including XRCC1 (rs25487 G>A), hOGG1 (rs1052133 C>G), MUTYH (rs3219489 G>C), XPA (rs1800975 G>A), ERCC2 (rs1799793 G>A) and XRCC3 (rs861539 C>T). Kaplan- Meier survival curve and Cox proportional hazards regression analyses were performed. SNP-SNP interaction was also examined using the survival tree analysis. RESULTS: Advanced disease stage and older age at diagnosis were associated with poor prognosis of NSCLC. Patients with the variant 'G' allele of hOGG1 rs1052133 had poor overall survival compared with those with the homozygous wild 'CC' genotype, especially in female patients, adenocarcinoma histology, early stage, light smokers and without family history of cancer. For never smoking female lung cancer patients, individuals carrying homozygous variant 'AA' genotype of XPA had shorter survival time compared to those with wild 'G' alleles. Furthermore, females carrying homozygous variant XPA and hOGG1 genotypes simultaneously had 2.78-fold increased risk for death. Among all 6 polymorphisms, the homozygous variant 'AA' of XPA carriers had poor prognosis compared to the carriers of wild 'G' alleles of XPA together with other base excision repair (BER) polymorphisms. CONCLUSIONS: Besides disease stage and age, the study found DNA repair gene polymorphisms were associated with lung cancer survival.

The incidence of lung cancer by histological type: a population-based study in Tianjin, China during 1981-2005.

BACKGROUND AND OBJECTIVE: Lung cancer remains the leading cause of cancer deaths worldwide. The aim of this study was to examine the trend in the incidence of lung cancer, validated by histology in Tianjin, the third largest municipal city in China, during the period from 1981 to 2005. METHODS: New lung cancer cases, crude incidence rates and age-adjusted rates by histological type were analysed using the data from the Tianjin Cancer Registry, which covers a population of 4 million urban residents. RESULTS: The most common histological types of lung cancer were squamous cell carcinoma (SQCC) in men and adenocarcinoma (ADC) in women. During the 25-year period, the constitutive pattern of the histological types changed gradually, ADC increased by 31.4%, but SQCC decreased by 25.6% among women. For SQCC, ADC or small cell carcinoma (SMCC), both the new cases and crude incidences per year increased among men and women. However, the age-adjusted incidences of all types of lung cancer showed an initial increase, which then levelled off or declined in recent years. The birth-cohort incidence analyses revealed that SQCC declined sharply, while ADC still increased among the younger age groups. CONCLUSION: The incidences of lung cancer by histological type changed during the 25-year period in Tianjin. Tailored strategies on prevention and control should be developed to meet the needs for various populations.

A Novel Porphyromonas gingivalis Infection-Related Inflammatory Response-Related Genes Signature Predicts the Prognosis of Esophageal Squamous Cell Carcinoma.

Background: Our previous research showed that Porphyromonas gingivalis (P. gingivalis) infection can activate the inflammatory signaling pathway and promotes the malignancy development of esophageal squamous cell carcinoma (ESCC). However, the prognostic significance of inflammatory response-related genes (IRRGs) in P. gingivalis-infected ESCC requires further elucidation. Hence, our study constructed a prognostic signature based on P. gingivalis and IRRGs to forecast the survival of patients with ESCC, which may provide insight into new treatment options for ESCC patients. Methods: Differentially expressed genes (DEGs) were identified in P.gingivalis-infected and P.gingivalis-uninfected ESCC cell by RNA sequencing. A risk model was constructed and validated using the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database by using univariate Cox regression analysis, LASSO, and the multivariate Cox regression analysis. Kaplan-Meier analysis was carried out to compare the overall survival (OS) between high-risk and low-risk groups. Single-sample gene set enrichment analysis was used to analyze the immune cell infiltration. The Genomics of Drug Sensitivity in Cancer database was used to predict drug sensitivity. Results: There were 365 DEGs between the P.gingivalis-infected and P.gingivalis-uninfected groups. Four genes including DKK1, ESRRB, EREG, and RELN were identified to construct the prognostic risk model (P = .012, C-index = 0.73). In both the training and validation sets, patients had a considerably shorter OS in the high-risk group than those in the low-risk group (P < .05). A nomogram was established using the risk score, gender, and N stage which could effectively forecast the prognosis of patients (P = .016, C-index = 0.66). The high-risk group displayed lower immune infiltrating cells, such as activated dendritic cells, type 2 T helper cells, and neutrophils (P < .05). A total of 41 drugs, including dactinomycin, luminespib, and sepantronium bromide, had a significant difference in IC50 between the 2 subgroups. Conclusion: We demonstrated the potential of a novel signature constructed from 4 P. gingivalis-related IRRGs for prognostic prediction in ESCC patients.

Clinical Significance of Porphyromonas gingivalis Enriching Cancer Stem Cells by Inhibiting Programmed Cell Death Factor 4 in Esophageal Squamous Cell Carcinoma.

Studies have confirmed that the colonization of Porphyromonas gingivalis (Pg) could promote the malignant evolution of esophageal squamous cell carcinoma (ESCC). Since pathogenic microorganisms can promote malignant tumor proliferation by inhibiting programmed cell death factor 4 (PDCD4) and the decrease of PDCD4 activity can enhance the stemness of cancer cells, we here investigated the functional mechanism by which Pg promoted ESCC chemoresistance and malignancy through inhibiting PDCD4 and enriching cancer stem cells (CSCs). The effects of Pg and PDCD4 on CSCs, chemoresistance and malignancy of ESCC cells were evaluated by in vitro studies. The expression of Pg, PDCD4, and ALDH1 in ESCC tissues were detected by IHC, and the correlations between each index and postoperative survival of ESCC patients were analyzed. The results showed that Pg could inhibit PDCD4 expression and lead to CSCs enrichment in ESCC cells. After eliminating Pg, the expression of PDCD4 was upregulated, the percentage of CSCs, chemoresistance and malignancy were decreased. ESCC patients with Pg-positive, PDCD4-negative, and ALDH1-positive have a significant shorter survival. This study proved that eliminating Pg and blocking CSCs enrichment caused by decreasing PDCD4 activity may provide a new strategy for ESCC treatment.

Porphyromonas gingivalis promotes malignancy and chemo-resistance via GSK3ß-mediated mitochondrial oxidative phosphorylation in human esophageal squamous cell carcinoma.

Our prior studies have confirmed that long-term colonization of Porphyromonas gingivalis (Pg) and overexpression of the inflammatory factor glycogen synthase kinase 3ß (GSK3ß) promote the malignant evolution of esophageal squamous cell carcinoma (ESCC). We aimed to investigate the functional mechanism by which Pg could promote ESCC malignancy and chemo-resistance through GSK3ß-mediated mitochondrial oxidative phosphorylation (mtOXPHOS), and the clinical implications. The effects of Pg and GSK3ß on mtOXPHOS, malignant behaviors and response to paclitaxel and cisplatin treatment of ESCC cells were evaluated by in vitro and in vivo studies. The results showed that Pg induced high expression of the GSK3ß protein in ESCC cells and promoted the progression and chemo-resistance via GSK3ß-mediated mtOXPHOS in human ESCC. Then, Pg infection and the expression of GSK3ß, SIRT1 and MRPS5 in ESCC tissues were detected, and the correlations between each index and postoperative survival of ESCC patients were analysed. The results showed that Pg-positive ESCC patients with high-expression of GSK3ß, SIRT1 and MRPS5 have significant short postoperative survival. In conclusion, we demonstrated that the effective removal of Pg and inhibition of its promotion of GSK3ß-mediated mtOXPHOS may provide a new strategy for ESCC treatment and new insights into the aetiology of ESCC.

Fusobacterium nucleatum induces MDSCs enrichment via activation the NLRP3 inflammosome in ESCC cells, leading to cisplatin resistance.

BACKGROUND: To analyse the regulatory effect of Fusobacterium nucleatum (Fn) on NOD-like receptor protein 3 (NLRP3) and myeloid-derived suppressor cells (MDSCs) in oesophageal squamous cell carcinoma (ESCC) as well as its effect on cisplatin (CDDP) therapy and to explore its clinical significance. METHODS: Fn infection, NLRP3 expression and MDSCs infiltration in ESCC tissues were detected by RNAscope and immunohistochemistry (IHC). The correlation between these three factors and the clinicopathological features and survival of ESCC patients was analysed. A coculture system of human peripheral blood monocytes (PBMCs) and ESCC cells was established to simulate the tumour microenvironment. In vitro and in vivo models were used to analyse the effects of Fn on the percentage of MDSCs in the coculture system and the NLRP3 expression level and CDDP sensitivity of ESCC cells. RESULTS: Fn infection was consistent with high NLRP3 expression and MDSCs enrichment in ESCC tissues. Moreover, the survival time of ESCC patients was significantly shortened under Fn infection, high NLRP3 expression and MDSCs enrichment. In the in vitro and in vivo models, Fn induced abundant enrichment of MDSCs by inducing high expression of NLRP3 in ESCC cells and reducing the sensitivity of ESCC cells to CDDP. CONCLUSIONS: Fn infection can induce high expression of NLRP3 in ESCC, lead to MDSCs enrichment, weaken the body's antitumour immunity, and lead to CDDP treatment resistance. The effective elimination of Fn and the inhibition of MDSCs enrichment may provide new strategies and treatments for ESCC.HighlightsThe survival of ESCC patients with Fn infection, high NLRP3 expression and MDSCs enrichment was significantly shortened.Fn infection could cause CDDP resistance in ESCC.Fn could induce the enrichment of MDSCs in the tumour microenvironment by activating NLRP3 in ESCC cells.

Effect of aerobic exercise on acquired gefitinib resistance in lung adenocarcinoma.

Lung adenocarcinoma patients with epidermal growth factor receptor (EGFR)-activating mutations respond well to tyrosine kinase inhibitors but typically develop resistance. Current therapies mainly target differentiated cells, not cancer stem cells (CSCs), but CSCs affect the occurrence, invasion, metastasis and treatment sensitivity of malignant tumours. Recently, aerobic exercise has emerged as adjuvant therapy for cancer. Aerobic exercise can accelerate blood circulation, improve tissue oxygen supply, reduce the stress level of patients, improve the antioxidant capacity of the body, and facilitate the degradation of hypoxia-inducible factor-1 (HIF-1) in tumour tissues, thus weakening its maintenance effect on CSCs. In this study, we successfully established lung adenocarcinoma cell lines with gefitinib resistance. Long-term gefitinib induction could increase the level of oxidative stress in lung adenocarcinoma cells and reduce the antioxidant capacity, resulting in the high expression of HIF-1 and ALDH1 and leading to the enrichment of CSCs, and a decreased response to gefitinib. This may be one of the important reasons for gefitinib-acquired resistance in lung adenocarcinoma. In the case of drug resistance, effective aerobic exercise could reduce ROS, activate SOD, inhibit HIF-1 and ALDH1, and cause a reduction in CSCs to sensitise cells to gefitinib again and ultimately inhibit the malignant proliferation of tumours. Therefore, in the treatment of lung adenocarcinoma, the inhibitory effect of aerobic exercise on oxidative stress can enhance the response of drug-resistant cells to gefitinib and can be used as an effective adjunct measure in the treatment of lung adenocarcinoma.

Frequencies of Porphyromonas gingivalis Detection in Oral-Digestive Tract Tumors.

Mounting evidence suggests a causal relationship between specific bacterial infections and the development of certain malignancies. In this study, we examined the presence of Porphyromonas gingivalis (P. gingivalis) in oral-digestive tract tumors by immunohistochemistry (IHC) and PCR and analyzed the correlation between P. gingivalis detection and clinicopathological characteristics and prognosis of oral and esophageal carcinoma. The IHC results showed that the positive rates of P. gingivalis were 60.00, 46.00, 20.00, 6.67, and 2.86% in oral, esophagus, cardiac, stomach, and colorectal cancer tissues, respectively. Likewise, PCR results showed rates of 56.00, 42.00, 16.67, 3.33, and 2.86%, respectively. The two methods were consistent, and the kappa value was 0.806, P < 0.001. In addition, P. gingivalis expression was significantly correlated with lymph node metastasis and the clinical stages of oral and esophageal cancer (P < 0.05). The overall survival rate of the P. gingivalis undetected group (86, 50%) was significantly higher than that of the P. gingivalis detected group (57, 14%) for oral and esophageal cancer, respectively. In conclusion, the detection rate of P. gingivalis showed a decreasing trend in oral-digestive tract tumors. Detection with P. gingivalis was associated with poor prognosis for oral and esophageal cancer.

Clinical Significance of Fusobacterium nucleatum Infection and Regulatory T Cell Enrichment in Esophageal Squamous Cell Carcinoma.

A variety of pathogenic microorganisms promote tumor occurrence and development through long-term colonization in the body. Fusobacterium nucleatum (F. nucleatum) is abundant in precancerous esophageal lesions and is closely related to the malignant progression of esophageal squamous cell carcinoma (ESCC). The invasion of exogenous microorganisms can reshape the immune microenvironment, make the immune system incapacitated, and assist tumor cells in immune escape. A variety of pathogenic microorganisms induce the recruitment of regulatory T cell (Tregs) to allow tumor cells to escape immune surveillance and provide favorable conditions for their own long-term colonization. Tregs are one of the major obstacles to tumor immunotherapy and have a significant positive correlation with the occurrence and development of many kinds of tumors. Because F. nucleatum can instantly enter cells and colonize for a long time, we speculated that F. nucleatum infection could facilitate the immune escape of tumor cells through enrichment of Tregs and promote the malignant progression of ESCC. In this study, we found a significant concordance between F. nucleatum infection and Tregs infiltration. Therefore, we propose the view that chronic infection of F. nucleatum may provide favorable conditions for long-term colonization of itself by recruiting Tregs and suppressing the immune response. At the same time, the massive enrichment of Treg may also weaken the immune response and assist in the long-term colonization of F. nucleatum. We analyzed the correlation between F. nucleatum infection with the clinicopathological characteristics and survival prognosis of the patients. F. nucleatum infection was found to be closely related to sex, smoking, drinking, degree of differentiation, depth of invasion, lymph node metastasis, and clinical stage. The degree of differentiation, depth of infiltration, lymph node metastasis, clinical stage, and F. nucleatum infection are independent risk factors affecting ESCC prognosis. Additionally, the survival rate and median survival time were significantly shortened in the F. nucleatum infection positive group. Therefore, we propose that long-term smoking and alcohol consumption cause poor oral and esophageal environments, thereby significantly increasing the risk of F. nucleatum infection. In turn, F. nucleatum infection and colonization may weaken the antitumor immune response through Treg enrichment and further assist in self-colonization, promoting the malignant progression of ESCC.

Associations of Porphyromonas gingivalis Infection and Low Beclin1 Expression With Clinicopathological Parameters and Survival of Esophageal Squamous Cell Carcinoma Patients.

Purpose: The present study focused on exploring the associations of Porphyromonas gingivalis (P. gingivalis) infection and low Beclin1 expression with clinicopathological parameters and survival of esophageal squamous cell carcinoma (ESCC) patients, so as to illustrate its clinical significance and prognostic value. Methods: Immunohistochemistry (IHC) was used to detect P. gingivalis infection status and Beclin1 expression in 370 ESCC patients. The chi-square test was adopted to illustrate the relationship between categorical variables, and Cohen's kappa coefficient was used for correlation analysis. Kaplan-Meier survival curves with the log-rank test were used to analyse the correlation of P. gingivalis infection and low Beclin1 expression with survival time. The effects of P. gingivalis infection and Beclin1 downregulation on the proliferation, migration and antiapoptotic abilities of ESCC cells in vitro were detected by Cell Counting Kit-8, wound healing and flow cytometry assays. For P. gingivalis infection of ESCC cells, cell culture medium was replaced with antibiotic-free medium when the density of ESCC cells was 70-80%, cells were inoculated with P. gingivalis at a multiplicity of infection (MOI) of 10. Result: P. gingivalis infection was negatively correlated with Beclin1 expression in ESCC tissues, and P. gingivalis infection and low Beclin1 expression were associated with differentiation status, tumor invasion depth, lymph node metastasis, clinical stage and prognosis in ESCC patients. In vitro experiments confirmed that P. gingivalis infection and Beclin1 downregulation potentiate the proliferation, migration and antiapoptotic abilities of ESCC cells (KYSE150 and KYSE30). Our results provide evidence that P. gingivalis infection and low Beclin1 expression were associated with the development and progression of ESCC. Conclusion: Long-term smoking and alcohol consumption causes poor oral and esophageal microenvironments and ESCC patients with these features were more susceptible to P. gingivalis infection and persistent colonization, and exhibited lower Beclin1 expression, worse prognosis and more advanced clinicopathological features. Our findings indicate that effectively eliminating P. gingivalis colonization and restoring Beclin1 expression in ESCC patients may contribute to preventation and targeted treatment, and yield new insights into the aetiological research on ESCC.

Clinical significance and prognostic value of Porphyromonas gingivalis infection in lung cancer.

A variety of pathogenic microorganisms can promote the occurrence and development of malignant tumors by colonizing in the body. It has been shown that Porphyromonas gingivalis (P. gingivalis) can be colonized for a long time in upper gastrointestinal tumors and is closely related to the occurrence and development of esophageal cancer in previous studies of our team. Because the esophagus and trachea are closely adjacent and P. gingivalis can instantly enter and colonize in cells, we speculate that P. gingivalis may be colonized in lung cancer cells through oral or blood, promoting the malignant progression of lung cancer. In this study, we investigated P. gingivalis infection in lung carcinoma tissues and adjacent lung tissues, and found that the colonization rate of P. gingivalis in carcinoma tissues was significantly higher than that in adjacent lung tissues. Therefore, we propose that the microenvironment of cancer cells is more conducive to the survival of P. gingivalis. Then, we analyzed the correlation between P. gingivalis infection and clinicopathological features and survival prognosis of patients with lung cancer. It was found that P. gingivalis infection was closely related to smoking, drinking, lymph node metastasis and clinical stage. Moreover, the survival rate and median survival time of patients with P. gingivalis infection were significantly shortened. Therefore, we put forward the view that long term smoking and drinking will cause a bad oral environment, increasing the risk of P. gingivalis infection, then P. gingivalis infection will promote the malignant progression of lung cancer.

MicroRNA-320d regulates tumor growth and invasion by promoting FoxM1 and predicts poor outcome in gastric cardiac adenocarcinoma.

Recent evidences demonstrate that dysregulated expression of microRNA-320d (miR-320d) has been associated with several cancer development and progression. However the effect of miR-320d on gastric cardiac adenocarcinoma (GCA) and the association of miR-320d with its potential gene target FoxM1 remain unclear. Here, we evaluated expression profile of miR-320d and FoxM1 in 60 human GCA tissues and GCA cell lines (OE-19 and SK-GT2). Immunohistochemistry, qualitative PCR and western-blotting were performed in GCA tissues to detect the expression level of miR-320d and FoxM1. CCK-8, transwell, wound-healing assays, and in vivo experiments were conducted using GCA cells that treated with miR-320d mimics or inhibitors to evaluate the biological functions of miR-320d. Luciferase reporter assay was conducted to confirm possible binding sites of FoxM1 for miR-320d. Compared with paired non-cancerous tissues, it showed that miR-320d expression was significantly decreased in GCA specimens (P < 0.0001), while FoxM1 was significantly upregulated in GCA tissues (P < 0.0001). Modulating miR-320d function by transfection of miR-320 mimics or inhibitor led to inhibition or promotion of GCA cell proliferation and invasion, thus regulating tumor progression in GCA-tumor bearing mice. The mechanism analysis of miR-320d/FoxM1 showed that FoxM1 has two miR-320d binding sites in its 3'-untranslated region (3'-UTR), that contributes to regulation of the cell biological behaviors. Taken together, our data suggested that miR-320d acts as a tumor suppressor in GCA by directly targeting FoxM1 and thus potentially serves as a biomarker for anti-GCA therapy in GCA patients.

Genetic Polymorphisms in the Vitamin D Pathway and Non-small Cell Lung Cancer Survival.

Various genetic polymorphisms have been linked to lung cancer susceptibility and survival outcomes. Vitamin D (VD) regulates cell proliferation and differentiation, inhibits tumor growth and induces apoptosis. Observations from several previous studies including our own suggest that genetic polymorphisms in the VD pathway may be associated with lung cancer risk. The aim of this study is to assess if genetic polymorphisms in the VD pathway are associated with the prognosis of non-small cell lung cancer (NSCLC). Nine single nucleotide polymorphisms (SNPs) in five genes in the VD pathway were genotyped with the TaqMan assays in 542 patients with primary NSCLC, and the relationships between these SNPs and overall survival were evaluated. We found that SNP rs10741657 in the CYP2R1 gene was associated with the prognosis of NSCLC, especially in elderly patients and not being treated with chemotherapy. Some of the VD pathway-related genetic polymorphisms may influence the prognosis of NSCLC. More research is needed to further confirm the finding and test if VD supplements can be used for NSCLC treatment.

Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma.

Lung adenocarcinoma (LAD) is a human malignancy successfully treated with the tyrosine kinase inhibitor (TKI) gefitinib; however, the enrichment of therapy resistant cancer stem cells (CSCs) in such patients is assumed to be a source of treatment failure. Evaluation of LAD cell populations treated with the TKI inhibitor gefitinib identified unique aspects of a subpopulation of tumor cells exhibiting stem-like properties and mitochondria-specific metabolic features along with their reliance on sirtuin 1 (SIRT1) for survival advantage. This addiction to bioenergetic metabolism in LAD treated with EGFR-targeted therapy suggests that mitochondrial targeting should be synthetically lethal using established cytotoxic therapies. Accordingly, loss of the phenotype present in resistant CSC clones either by targeting the energy metabolism with tigecycline, a mitochondrial DNA-translation inhibitor, or tenovin-6 (TV-6), a SIRT1 inhibitor, inhibited their dependency on mitochondrial oxidative phosphorylation (mtOXPHOS) and sensitized them for a more pronounced and long-lasting TKI therapeutic effect. The results specifically demonstrated that combined therapy with TV-6 and gefitinib resulted in tumor regression in xenograft mouse models, whereas administration of a single agent showed no such efficacy. Importantly, combined treatment with TV-6 also decreased the effective dose of gefitinib necessary for treatment response. Clinical analysis demonstrated that high-profile SIRT1 and mtOXPHOS proteins were associated with recurrence and poor prognosis in LAD patients. These observations support the CSC hypothesis for cancer relapse and advocate use of mitochondria-targeting inhibitors as part of combinatorial therapy in a variety of clinical settings, as well as for reducing first-line TKI dosage in LAD patients.