Auto-suppression of Tet dioxygenases protects the mouse oocyte genome from oxidative demethylation.

DNA cytosine methylation plays a vital role in repressing retrotransposons, and such derepression is linked with developmental failure, tumorigenesis and aging. DNA methylation patterns are formed by precisely regulated actions of DNA methylation writers (DNA methyltransferases) and erasers (TET, ten-eleven translocation dioxygenases). However, the mechanisms underlying target-specific oxidation of 5mC by TET dioxygenases remain largely unexplored. Here we show that a large low-complexity domain (LCD), located in the catalytic part of Tet enzymes, negatively regulates the dioxygenase activity. Recombinant Tet3 lacking LCD is shown to be hyperactive in converting 5mC into oxidized species in vitro. Endogenous expression of the hyperactive Tet3 mutant in mouse oocytes results in genome-wide 5mC oxidation. Notably, the occurrence of aberrant 5mC oxidation correlates with a consequent loss of the repressive histone mark H3K9me3 at ERVK retrotransposons. The erosion of both 5mC and H3K9me3 causes ERVK derepression along with upregulation of their neighboring genes, potentially leading to the impairment of oocyte development. These findings suggest that Tet dioxygenases use an intrinsic auto-regulatory mechanism to tightly regulate their enzymatic activity, thus achieving spatiotemporal specificity of methylome reprogramming, and highlight the importance of methylome integrity for development.

[Efficacy observation of accelerated hyperfractionation recourse radiotherapy plus concurrent capecitabine in the treatment of locoregional recurrent rectal cancer].

OBJECTIVE: To evaluate the efficacy of accelerated hyperfractionation (CAF) radiotherapy plus concurrent capecitabine in the treatment of locoregional recurrent rectal cancer. METHODS: Between June 2004 and January 2008, 53 patients with locoregional recurrent rectal cancer were treated with CAF 1.2 Gy/f, 2 f/d plus concurrent capecitabine at an oral dosage of 825 mg/m2 bid on each day of radiotherapy period. The first daily dose was applied at 2 h pre-irradiation, d1-14 and d22-35. After a regimen of 36 Gy/30 f/3 w, the feasibility of surgical resection was then evaluated by CT. Patients unsuitable for surgical resection continued CAF. And the total dose was 52.8-57.6 Gy. RESULTS: The complete response rate was 9.8%, the partial response rate 45.1%, the effective rate 54.9%, the no-change rate 29.4%, the progression rate 15.7%, the surgical resection rate 23.5% and the R0, R1 resection rates 21.6% and 1.9% respectively. The Time to Progression was 10.5 months, 1-year survival rate was 84.3%, 2-year survival rate was 61.1%. Quality of life improved in treatment group. Toxic and adverse effects were gastrointestinal and hematological toxicities. There was no treatment-related mortality. CONCLUSION: The 3-dimensional conformal radiotherapy plus concurrent chemotherapy may be an effective and well-tolerated regimen in patients with postoperative locoregional recurrent or metastatic rectal cancer.

[Efficacy of oxaliplatin plus 5-fluorouracil/leucovorin calcium combined with concurrent radiotherapy for local advanced gastric cancer].

OBJECTIVE: To evaluate the efficacy of r oxaliplatin plus 5-fluorouracil/leucovorin calcium (LV) combined with concurrent radiotherapy in the treatment of local advanced gastric cancer. METHODS: 83 patients with local advanced gastric cancer were randomized into 2 groups. Group I (n = 40) underwent irradiation at the dose of 40 - 45 Gy 5 times a week on the primary tumor and the lymph nodes with the size > or = 10 mm in short axis, and receiving intravenous drip of OXA 85 mg/m2 for 2 h, intravenous injection of LV 200 mg/m2, and then intravenous injection of 5-fu 300 mg/m2, followed by continuous intravenous infusion of 5-fu 500 mg/m2, for 22 h, with 2 weeks as a cycle. Three cycles of chemotherapy were given during the radiotherapy. Then operative evaluation was conducted. Those resectable underwent operation and then 3 cycles of adjuvant chemotherapy. Those un-resectable underwent continuous 3 cycles of chemotherapy. Group II (n = 43) received only chemotherapy. The treatment was repeated until disease progression or prohibitive toxicity. RESULTS: 38 patients were evaluated in Group I, the result showed complete remission (CR) in 4 patients (10.5%), partial remission (PR) in 23(60.5%), no-change (NC) in 7(18.4%), progressive disease (PD) in 5(13.2%), with the remission rate (RR) of 71% (27/40). 42 patients were evaluated in Group II, the result showed CR in 3 patients (7.14%), PR in 16(14.3%), NC in 13(30.9%), and PD in 9(26.2%)with the RR of 45% (19/43). The resection rates of Groups I and II were 32.5% and 27.9% respectively (P = 0.649). The R0 resection rates of Groups I and II were 77.8% and 57.1% respectively (P = 0.161). The mean survival times of the resectable patients in Groups I and II were 45 months and 28 months respectively, and the 2-year overall survival (OS) of the resectable patients in Groups I and II were 65.8% and 56.3% respectively (P = 0.371). The mean survival times of the un-resectable patients in Groups I and II were 14 months and 9 months respectively, and the 2-year OS rates of the un-resectable patients in Groups I and II were 28.3% and 20.7% respectively (P = 0.017). The toxic and adverse effects included gastrointestinal and hematological toxicity. There was no treatment-related death. CONCLUSION: Radiotherapy combined with concurrent chemotherapy may be an effective and well-tolerated regimen in patients with advanced and metastatic gastric cancer.

[Combination of docetaxel and capecitabine for the treatment of anthracycline-resistant advanced breast carcinoma].

OBJECTIVE: To evaluate the efficacy and toxicity of docetaxel and capecitabine combination in the treatment of anthracycline-resistant advanced breast carcinoma. METHODS: Forty-three patients with anthracycline-resistant advanced breast carcinoma were treated with docetaxel combined with capecitabine between January 2002 and November 2004. Docetaxel was administered intravenously at a dose of 75 mg/m(2) on D1, and oral intake of capecitabine at a dose of 1600 mg/d on D1 to D14, every 21 days as a cycle. The median number of cycles was 4 (range, 4 approximately 6 cycles). RESULTS: All the 43 patients had a mean follow-up of 15 months. The overall response rate was 62.8%, with a complete response rate of 20.9% and partial response rate of 44.2%. The median survival time was 15 months with a median time to progression of 7.5 months. The one-year and 2-year survival rates were 62.8% and 41.9%, respectively. The quality of life was improved in all patients. The major toxicity and adverse effects were gastrointestinal reaction and hematological toxicity. CONCLUSION: The combination of docetaxel and capecitabine for the treatment of anthracycline-resistant advanced breast carcinoma is effective, safe and tolerable.