HPV16 infection promotes an M2 macrophage phenotype to promote the invasion and metastasis of esophageal squamous cell carcinoma

Objectives High-risk human papillomavirus (HR-HPV) is an important risk factor for esophageal cancer. Macrophages constitute a crucial immune medium for regulating HPV-related tumors; however, the specific regulatory mechanisms remain unknown. Therefore, the purpose of our current study was to investigate the mechanism by which HPV16E6 regulates macrophages to promote the invasion and metastasis of esophageal cancer. Methods HPV16E6 infection was detected by polymerase chain reaction. Immunohistochemistry was used to verify the distribution of tumor-associated macrophages (TAMs) and MMP-9 expression in esophageal squamous cell carcinoma tissues (ESCCs), and cancer adjacent normal tissues (CANs) from Kazakh patients. ESCC cells were transfected with a plasmid over-expressing HPV16E6 and non-contact cocultured with macrophages. Results The infection rate of HPV16E6 in Kazakh ESCCs was clearly higher than that in CANs (P < 0.05). The density of CD163-positive TAMs was significantly positively correlated with HPV16E6 infection in ESCCs (P < 0.05). After coculturing macrophages and EC9706 cells transfected with the HPV16E6 plasmid, the phenotype of macrophages transformed into M2 macrophages. The migration and invasion ability of ESCC cells were higher in the HPV16E6-transfected and coculture group than in the HPV16E6 empty vector-transfected and non-cocultured HPV16E6-transfected groups (all P < 0.05). The density of M2-like TAMs in ESCCs was positively correlated with the level of MMP-9 expression. MMP-9 expression in the HPV16E6-ESCC coculture macrophages group was substantially higher than that in controls (all P < 0.05). Conclusions HPV16 infection mediates tumor-associated macrophages to promote ESCC invasion and migration (AU)

HPV16 infection promotes an M2 macrophage phenotype to promote the invasion and metastasis of esophageal squamous cell carcinoma.

OBJECTIVES: High-risk human papillomavirus (HR-HPV) is an important risk factor for esophageal cancer. Macrophages constitute a crucial immune medium for regulating HPV-related tumors; however, the specific regulatory mechanisms remain unknown. Therefore, the purpose of our current study was to investigate the mechanism by which HPV16E6 regulates macrophages to promote the invasion and metastasis of esophageal cancer. METHODS: HPV16E6 infection was detected by polymerase chain reaction. Immunohistochemistry was used to verify the distribution of tumor-associated macrophages (TAMs) and MMP-9 expression in esophageal squamous cell carcinoma tissues (ESCCs), and cancer adjacent normal tissues (CANs) from Kazakh patients. ESCC cells were transfected with a plasmid over-expressing HPV16E6 and non-contact cocultured with macrophages. RESULTS: The infection rate of HPV16E6 in Kazakh ESCCs was clearly higher than that in CANs (P < 0.05). The density of CD163-positive TAMs was significantly positively correlated with HPV16E6 infection in ESCCs (P < 0.05). After coculturing macrophages and EC9706 cells transfected with the HPV16E6 plasmid, the phenotype of macrophages transformed into M2 macrophages. The migration and invasion ability of ESCC cells were higher in the HPV16E6-transfected and coculture group than in the HPV16E6 empty vector-transfected and non-cocultured HPV16E6-transfected groups (all P < 0.05). The density of M2-like TAMs in ESCCs was positively correlated with the level of MMP-9 expression. MMP-9 expression in the HPV16E6-ESCC coculture macrophages group was substantially higher than that in controls (all P < 0.05). CONCLUSIONS: HPV16 infection mediates tumor-associated macrophages to promote ESCC invasion and migration.

Genomic origin and EGFR-TKI treatments of pulmonary adenosquamous carcinoma.

BACKGROUND: Adenosquamous carcinoma (ASC) of the lung is a heterogeneous disease that is composed of both adenocarcinoma components (ACC) and squamous cell carcinoma components (SCCC). Their genomic profile, genetic origin, and clinical management remain controversial. PATIENTS AND METHODS: Resected ASC and metastatic tumor in regional lymph nodes (LNs) were collected. The ACC and SCCC were separated by microdissection of primary tumor. The 1021 cancer-related genes were evaluated by next-generation sequencing independently in ACC and SCCC and LNs. Shared and private alterations in the two components were investigated. In addition, genomic profiles of independent cohorts of adenocarcinomas and squamous cell carcinomas were examined for comparison. We have also carried out a retrospective study of ASCs with known EGFR mutation status from 11 hospitals in China for their clinical outcomes. RESULTS: The most frequent alterations in 28 surgically resected ASCs include EGFR (79%), TP53 (68%), MAP3K1 (14%) mutations, EGFR amplifications (32%), and MDM2 amplifications (18%). Twenty-seven patients (96%) had shared variations between ACC and SCCC, and pure SCCC metastases were not found in metastatic LNs among these patients. Only one patient with geographically separated ACC and SCCC had no shared mutations. Inter-component heterogeneity was a common genetic event of ACC and SCCC. The genomic profile of ASC was similar to that of 170 adenocarcinomas, but different from that of 62 squamous cell carcinomas. The incidence of EGFR mutations in the retrospective analysis of 517 ASCs was 51.8%. Among the 129 EGFR-positive patients who received EGFR-TKIs, the objective response rate was 56.6% and the median progression-free survival was 10.1 months (95% confidence interval: 9.0-11.2). CONCLUSIONS: The ACC and SCCC share a monoclonal origin, a majority with genetically inter-component heterogeneity. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR TKI.

[Developmental expression of Arabidopsis methyltransferase genes MET1, DRM2 and CMT3].

Cytosine methylation is an epigenetic mark found in the genome of fungi, plants, and animals. DNA methylation is catalyzed by DNA methyltransferases. The function of DNA methyltransferases was shown to be highly conversed, but biological role of these enzymes has not been clearly defined. We generated transgenic plants expressing METHYLTRANSFERASES::GUS reporter genes for three major DNA methyltransferases (MET1, DRM2 and CMT3) to gain insight into the potential physiological relevance of the distinct members of the DNA methyltransferase family in Arabidopsis thaliana, and to investigate the expression patterns in detail. We found that METHYLTRANSFERASE::GUS genes display unique tissue, cell-type, and temporal patterns of expression throughout normal development, particularly in the flower. Our findings are supported by semi-quantitative reverse-transcription PCR, as well as by analyses of microarray databases. These data suggest that DNA methyltransferase may contribute to morphogenesis at every developmental stage and in every plant organ.

Long-term follow-up of a phase III study comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: Previous results from our trial showed that adding oxaliplatin to radiotherapy (RT) increased survival in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term efficacy and late toxic effects. PATIENTS AND METHODS: Between January 2001 and January 2003, 115 Patients with nonkeratinizing/undifferentiated locoregionally advanced NPC were randomly to receive either RT alone (n = 56) or plus concurrent oxaliplatin 70 mg/m(2) weekly for six cycles (n = 59). RESULTS: After a median follow-up of 114 months (range 18-139 months), the 5-year overall survival (OS) and metastasis-free survival (MFS) rates in the concurrent chemoradiotherapy (CCRT) group were significantly higher than those observed in the RT-alone group (OS, 73.2% versus 60.2%, P = 0.028; MFS, 74.7% versus 63.0%, P = 0.027). However, CCRT did not improve locoregional failure-free survival significantly. Subgroup analyses showed that the superiorities of CCRT mainly existed in the T3-4N0-1 stage subgroup (OS: HR = 0.394, P = 0.034). The grade 3/4 late toxic effects were similar in the two groups. CONCLUSION(S): The long-term follow-up data confirms the role of CCRT as a treatment of locoregionally advanced NPC. Oxaliplatin can be considered as an alternative optional therapeutic regimen for these patients due to its high efficiency and low toxic effect.

Human papillomavirus type 16 infection may be involved in esophageal squamous cell carcinoma carcinogenesis in Chinese Kazakh patients.

The aim of this study was to investigate human papillomavirus type 16 (HPV16) prevalence in esophageal squamous cell carcinoma (ESCC) in Xinjiang Kazakh patients and its role in ESCC carcinogenesis. One hundred and fifty cases of ESCC and 150 cases of corresponding normal esophageal mucosa (CNGM) samples were collected from north Xinjiang where the Kazakh ethnic group has lived since ancient times. HPV16 infection in ESCC and CNGM was detected by genotype-specific polymerase chain reaction. HPV16 DNA was detected in 55 of 150 ESCC samples (36.7%) and 24 of 150 corresponding normal esophageal mucosa samples (16%) with significant differences (P < 0.001, odds ratio = 3.039, 95% confidence interval: 1.756-5.260). No statistically significant correlations were found between HPV16 infection and the age or gender of patients, tumor site, tumor cell differentiation, or lymph node metastasis (P > 0.05). HPV16 infection is common in cases of ESCC in the Kazakh ethnic group in Xinjiang and may be involved in ESCC carcinogenesis.

Congenital muscular dystrophy: report of one case.

A case is reported of a newborn who presented with generalized hypotonia shortly after delivery. Creatine kinase (CK) was highly elevated. Muscle biopsy of the rectus femoris muscle revealed varying sized muscle fibers, displacement by fat and connective tissues, necrosis and regeneration of the muscle fibers. Magnetic resonance imaging (M.R.I.) of the brain showed normal development, compatible with the patient's age. Congenital muscular dystrophy was diagnosed from clinical manifestations, laboratory findings, and the results of muscle biopsy.