Fragile X mental retardation protein promotes astrocytoma proliferation via the MEK/ERK signaling pathway.

OBJECTIVE: To examine the association between fragile X mental retardation protein (FMRP) expression and astrocytoma characteristics. METHODS: Pathologic grade and expressions of glial fibrillary acidic protein (GFAP), Ki67 (proliferation marker), and FMRP were determined in astrocytoma specimens from 74 patients. Kaplan-Meier survival analysis was undertaken. Pathologic grade and protein levels of FMRP were determined in 24 additional patients with astrocytoma and 6 controls (cerebral trauma). In cultured U251 and U87 cell lines, the effects of FMRP knock-down on cell proliferation, AKT/mTOR/GSK-3ß and MEK/ERK signaling were studied. The effects of FMRP knock-down on the volumes and weights of U251 cell-derived orthotopic tumors in mice were investigated. RESULTS: In patients, FMRP expression was increased in grade IV (5.1-fold, P<0.01) and grade III (3.2-fold, P<0.05) astrocytoma, compared with controls. FMRP and Ki67 expressions were positively correlated (R2=0.877, P<0.001). Up-regulation of FMRP was associated with poorer survival among patients with FMRP integrated optical density >30 (P<0.01). In astrocytoma cell lines, FMRP knock-down slowed proliferation (P<0.05), inhibited total MEK levels P<0.05, and reduced phosphorylation of MEK (Ser217/221) and ERK (Thr202/Tyr204) (P<0.05). In mice with orthotopic tumors, FMRP knock-down decreased FMRP and Ki67 expressions, and reduced tumor volume and weight (36.3% or 61.5% on day 15, both P<0.01). Also, phosphorylation of MEK (Ser217/221) and ERK (Thr202/Tyr204), and total MEK in xenografts were decreased in sh-FMRP xenografts compared with non-transfected ones (all P<0.05). CONCLUSION: Enhanced FMRP expression in astrocytoma may promote proliferation through activation of MEK/ERK signaling.

Mast Cell Targeted Chimeric Toxin Can Be Developed as an Adjunctive Therapy in Colon Cancer Treatment.

The association of colitis with colorectal cancer has become increasingly clear with mast cells being identified as important inflammatory cells in the process. In view of the relationship between mast cells and cancer, we studied the effect and mechanisms of mast cells in the development of colon cancer. Functional and mechanistic insights were gained from ex vivo and in vivo studies of cell interactions between mast cells and CT26 cells. Further evidence was reversely obtained in studies of mast cell targeted Fcε-PE40 chimeric toxin. Experiments revealed mast cells could induce colon tumor cell proliferation and invasion. Cancer progression was found to be related to the density of mast cells in colonic submucosa. The activation of MAPK, Rho-GTPase, and STAT pathways in colon cancer cells was triggered by mast cells during cell-to-cell interaction. Lastly, using an Fcε-PE40 chimeric toxin we constructed, we confirmed the promoting effect of mast cells in development of colon cancer. Mast cells are a promoting factor of colon cancer and thus also a potential therapeutic target. The Fcε-PE40 chimeric toxin targeting mast cells could effectively prevent colon cancer in vitro and in vivo. Consequently, these data may demonstrate a novel immunotherapeutic approach for the treatment of tumors.

Experimental study on pulmonary cryoablation in a porcine model of normal lungs.

Objective of this study is to analyze the range of necrosis after using different freezing times and freeze-thaw cycles during percutaneous cryosurgery, in order to create a suggestion for optimizing the technique for lung cryoablation. Six healthy pigs were given a CT scan and histological investigation after percutaneous cryosurgery on both lungs. Three cryoprobes were inserted into both the left and right lungs of each pig, respectively. Cryoablation was performed with two cycles of an active 10-minute freezing using argon in the left lung, each freeze followed by an active 5-minute thaw using helium. In contrast to the left lung cryoablation, the right lungs underwent 3 cycles of freeze/thaw, the first and second cycles consisted of an active 5-minute freezing followed by an active 5-minute thaw, and the third cycle of 10-minute freezing and an active 5-minute thaw. The CT imaging change of an ice ball was continuously observed. The lung tissues were taken 4 hours after cryosurgery on day 3 and on day 7, respectively, for pathological observation. One pig presented acute symptoms including bradycardia and hypothermia 30 minutes after cryosurgery, and died 4 hours after the freezing, and the other 5 pigs experienced a weak condition for 4-6 hours and then exhibited relatively normal behavior and regularly took food. The freezing area (ice ball) on CT imaging during the cryoablation grew gradually in relation to the increase over time, and along with the increase in the number of cycles. The size of the cryolesion on the lung samples became larger than the ice ball during cryosurgery, regardless of whether 2 or 3 freeze-thaw cycles were performed. The area of necrosis histologically gradually increased for the time being. Percutaneous cryosurgery on the lung can achieve complete ablation of targeted tissue. Three freeze-thaw cycles are recommended, and the range of cryoablation may not be mandatory "1 cm safe border" during cryosurgery in order to avoid harming the organ and tissue which is close to the cancer. Correct use of the technique is especially important to treat the lung neoplasms, especially the malignant tumors, which are close to the heart and large vessels.

[Imaging and pathological features of percutaneous cryosurgery on normal lung evaluated in a porcine mode].

BACKGROUND AND OBJECTIVE: Lung cancer is one of the most commonly occurring malignancies and frequent causes of death in the world. Cryoablation is a safe and alternative treatment for unresectable lung cancer. Due to the lung being gas-containing organ and different from solid organs such as liver and pancreas, it is difficult to achieve the freezing range of beyond the tumor edge 1 cm safety border. The aim of this study is to examine the effect of different numbers of freeze cycles on the effectiveness of cryoablation on normal lung tissue and to create an operation guideline that gives the best effect. METHODS: Six healthy Tibetan miniature pigs were given a CT scan and histological investigation after percutaneous cryosurgery. Cryoablation was performed as 2 cycles of 10 min of active freezing in the left lung; each freeze followed by a 5 min thaw. In the right lung, we performed the same 2 cycles of 5 min of freezing followed by 5 min of thawing. However, for the right lung, we included a third cycle of consisting of 10 min of freezing followed by 5 min of thawing. Three cryoprobes were inserted into the left lung and three cryoprobes in the right lung per animal, one in the upper and two in the lower lobe, so as to be well away from each other. Comparison under the same experimental condition was necessary. During the experiment, observations were made regarding the imaging change of ice-ball. The lungs were removed postoperatively at 3 intervals: 4 h, 3 d of postoperation and 7 d of postoperation, respectively, to view microscopic and pathological change. RESULTS: The ice-ball grew gradually in relation to the increase in time, and the increase in number of cycles. The size of the cryolesion (hypothesis necrotic area) in specimens, over time, became larger in size than the size of the ice-ball during operation, regardless of whether 2 or 3 freeze-thaw cycles were performed. The area of necrosis was gradually increased over the course of time. The hypothesis necrotic area was equal to necrosis area 3 d after cryosurgery. CONCLUSIONS: Percutaneous cryoablation of the lung can achieve complete ablation of target tissue. The freezing technique may be different depending on the individual circumstances of each tumor. In technology, 3 freeze-thaw cycles are recommended, and the range of cryoablation's effective diameter may be not necessarily beyond the tumor edge at least 1 cm safe border during cryosurgery.

Germinoma in the basal ganglia with an abnormal karyotype: case report and review of the literature.

INTRODUCTION: Germ cell tumor of basal ganglia with abnormal constitutional karyotype has been rarely reported. CASE REPORT: A 9-year-old boy presented with precocious puberty and right hemiparesis. Magnetic resonance imaging showed high intensity on T1-weighted, T2-weighted, and contrast-enhanced T1-weighted images in the left basal ganglia and ipsilateral cerebral hemiatrophy predominantly in the basal ganglia and midbrain. Germinoma in the left basal ganglia was confirmed by stereotactic biopsy and immunochemical examination. His constitutional karyotype was 46, XY, t (8; 19), (p23.1; p13.1), a novel chromosomal abnormality. DISCUSSION: Intracranial germinoma, a potentially curable tumor, should be considered in children with nonspecific neurological symptoms, endocrinologic changes, and ipsilateral cerebral hemiatrophy on computed tomography or magnetic resonance. Investigation of chromosomal aberrations in those patients would clarify the tumorigenesis and lead to possibilities for novel disease-specific therapies.

The Epstein-Barr virus-associated gastric carcinoma in Southern and Northern China.

In the present study, we examined the proportions of Epstein-Barr virus-associated gastric carcinomas (EBV-GCs) in Guangzhou, southern China and Shenyang, northern China, two areas differing markedly in nasopharyngeal carcinoma (NPC) incidence. Using in situ hybridization assay, the presence of EBV-encoded small RNA (EBER) was examined in 198, and 180 gastric cancer cases in Guangzhou and Shenyang, respectively. The proportion of EBV-GC in Guangzhou (9%) was significantly higher than that in Shenyang (6%), and the odds ratio (OR) for Guangzhou, after adjusting for the effects of age, sex, and tumor subsite, was 2.7 (95% CI = 1.1-6.2) when Shenyang was taken as reference. There was a male predominance of EBV-GC, and the OR for male was 3.0 (95% CI = 1.2-7.3) when female was taken as reference. We observed a weak and negative age dependence in the proportion of EBV-GC (p-values for trend = 0.077). The EBV-GC was most commonly observed in the middle part of stomach in both series. The frequency of EBV-GCs was higher in cases with p53 overexpression than in cases without p53 expression (OR = 2.4, 95% CI = 1.0-5.8). Among p53-positive cases, the frequency of EBV-GC decreased as the proportion of p53-positive carcinoma cells increased (p for trend = 0.021). In conclusion, the present study suggested that the frequency of EBV-GC in Guangzhou, southern China, where NPC is the most common in the world, may be higher than that in other parts of China.