Epigenetic Co-Deregulation of EZH2/TET1 is a Senescence-Countering, Actionable Vulnerability in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) cells lack the expression of ER, PR and HER2. Thus, TNBC patients cannot benefit from hormone receptor-targeted therapy as non-TNBC patients, but can only receive chemotherapy as the systemic treatment and have a worse overall outcome. More effective therapeutic targets and combination therapy strategies are urgently needed to improve the treatment effectiveness. Methods: We analyzed the expression levels of EZH2 and TET1 in TCGA and our own breast cancer patient cohort, and tested their correlation with patient survival. We used TNBC and non-TNBC cell lines and mouse xenograft tumor model to unveil novel EZH2 targets and investigated the effect of EZH2 inhibition or TET1 overexpression in cell proliferation and viability of TNBC cells. Results: In TNBC cells, EZH2 decreases TET1 expression by H3K27me3 epigenetic regulation and subsequently suppresses anti-tumor p53 signaling pathway. Patients with high EZH2 and low TET1 presented the poorest survival outcome. Experimentally, targeting EZH2 in TNBC cells with specific inhibitor GSK343 or shRNA genetic approach could induce cell cycle arrest and senescence by elevating TET1 expression and p53 pathway activation. Using mouse xenograft model, we have tested a novel therapy strategy to combine GSK343 and chemotherapy drug Adriamycin and could show drastic and robust inhibition of TNBC tumor growth by synergistic induction of senescence and apoptosis. Conclusions: We postulate that the well-controlled dynamic pathway EZH2-H3K27me3-TET1 is a novel epigenetic co-regulator module and provide evidence regarding how to exploit it as a novel therapeutic target via its pivotal role in senescence and apoptosis control. Of clinical and therapeutic significance, the present study opens a new avenue for TNBC treatment by targeting the EZH2-H3K27me3-TET1 pathway that can modulate the epigenetic landscape.

[Laparoscopic anatomical hepatectomies for intrahepatic bile duct stone].

OBJECTIVE: To assess the feasibility and safety of laparoscopic anatomical hepatectomies (LAH) for intrahepatic bile duct stone. METHODS: LAH was performed in 14 patients with intrahepatic bile duct stone, while another 20 patients with intrahepatic bile duct stone underwent classical operation. Surgical time, blood loss, postoperative complications, and postoperative hospital stay were recorded. RESULTS: The operations were successful in all 14 patients who underwent LAH. Surgical time was 190-420 mm [mean (259 +/- 134) mm]. Blood loss during operation was 220-1 000 ml [mean (454.5 +/- 314.2) ml]. No serious postoperative complications occurred. All these 14 patients were discharged with T dragin 7-14 days later, and the mean postoperative hospital stay was (9.2 +/- 3.4) days. In the classical operation group, the surgical time was 125-257 mm [mean (178 +/- 58) mm] and the blood loss was 210-1200 ml [mean (550.9 +/- 348.1) ml] All the patients were discharged with T dragin 9-25 days after operation, and the mean postoperative hospital stay was (13.4 +/- 4.7) days. Surgical time of LAH was longer than classical operation (P < 0.05). Rate of postoperative complications and postoperative hospital stay were decreased in LAH (P < 0.05, P < 0.01). The difference of blood loss during operation was no significance between LAH and classical operation (P > 0.05). CONCLUSIONS: LAH is feasible and safe for selected patients with intrahepatic bile duct stones. As a minimally invasive procedure, it can reduce surgical time, blood loss, hospital stay, and postoperative complications.

Risk factors, treatment and impact on outcomes of bile leakage after hemihepatectomy.

BACKGROUND: Risk factors for bile leakage after hemihepatectomy are unknown. METHODS: A prospectively maintained database review identified patients undergoing hemihepatectomy between 1 January 2009 and 30 September 2014. Patients were divided into B/C and non-B/C bile leakage groups. Risk factors for bile leakage were predicted and assessments of their impact on patients were made. RESULTS: Bile leakage occurred in 91 of the 297 patients (30.6%); 64 cases were classified as grade B bile leakage (21.5%) and three cases as grade C bile leakage (1.0%). Multivariate analysis confirmed that elevated preoperative alanine transaminase (ALT), positive bile culture during surgery, hilar bile duct plasty, bilioenteric anastomosis and laparoscopic surgery were risk factors for B/C grade bile leakage (P < 0.05). Percutaneous transhepatic biliary drainage (PTBD) and endoscopic nasobiliary drainage (ENBD) were protective factors for B/C grade bile leakage (P < 0.05). PTBD, ENBD and Kehr's T-tube drainage could reduce the drainage volume and duration of drainage after bile leakage (P < 0.05). The incidence of wound infection, abdominal infection, major complications and the Clavien classification system score in the B/C bile leakage group were higher than those in the non-B/C bile leakage group (P < 0.05). Patients in the B/C bile leakage group also required prolonged hospitalization (P < 0.05). The mortality of two groups was similar (P > 0.05). CONCLUSION: Patient with elevated preoperative ALT, positive bile cultures during surgery, hilar bile duct plasty, bilioenteric anastomosis and laparoscopic surgery are more likely to complicate bile leakage. We should use biliary drainage such as preoperative PTBD, ENBD or intraoperative Kehr's T-tube drainage to reduce and treat bile leakage in patients with high risk of bile leakage.